Category Archives: Genetics

Genetics

Otago University Discovers Cause of Rare Genetic Condition – Mirage News

An international team of researchers has discovered what causes an unusual and incredibly rare genetic condition, giving hope to the families with it and others with related disorders.

Led by the University of Otago, with academics from across the USA, South Africa, UK and Europe, the study focused on the role of glutamine in brain development.

By analysing the effects genetic variants had on brain cells, they found the cause of a new rare condition Glutamine Synthetase Stabilization Disorder which causes seizures and delayed development. They have just published their findings in prestigious international journal The American Journal of Human Genetics.

Amy Jones

Lead author Amy Jones, PhD candidate in Otago's Dunedin School of Medicine, says the work started with one child with the condition.

"From there eight other individuals from around the world with disrupted brain development and severe epilepsy had their DNA sequenced and causative genetic variants were found. These variants were all positioned at the start of the same gene, prompting us to ask why," she says.

Molecular experiments revealed the genetic variants had the effect of producing a stabilised enzyme that produces the small molecule glutamine in an unregulated fashion.

"Typically, genetic disorders result from genetic variants that disable a gene, so it was surprising that in this case there was an increase in stability of the enzyme. In some ways these variants can be thought to be taking the handbrake off the enzyme and letting it free wheel in an unregulated fashion.

"This tells us that the production of glutamine needs to be maintained within a very tight specific range during brain development both too much and too little damages the developing brain," she says.

Senior author Professor Stephen Roberston, Cure Kids Professor of Paediatric Genetics, describes the study as "an excellent example of finely tuned precision medicine".

"All of these children were previously treated according to their symptoms rather than from an understanding of the cause of their condition.

"There are thousands of similar rare disorders, collectively affecting eight per cent of the general population and many of them are genetic. Defining their causes is the first logical step to formulating treatments specific to them to enable more effective management of the disorders," he says.

Ms Jones says it is important new disorders are discovered and understood.

"Not only does such research provide answers for the individuals and families who participated in this work but also enables the recognition and diagnosis of the same condition in the future.

"This work on a rare disorder also contributes to the collective knowledge of critical components of healthy brain development."

She hopes the findings will enable other individuals who fit the clinical profile, but don't have a diagnosis, to be tested for this disorder.

"It is very likely there are individuals with this disorder that aren't yet diagnosed."

Publication:

Clustered de novo Start-Loss Variants in GLUL Result in a Developmental and Epileptic Encephalopathy via Stabilization of Glutamine Synthetase

Amy G Jones, Matilde Aquilino, Rory J Tinker, Laura Duncan, Zandra Jenkins, Gemma L Carvill, Stephanie J DeWard, Dorothy K Grange, MJ Hajianpour,Benjamin J Halliday, Muriel Holder-Espinasse, Judit Horvath, Silvia Maitz, Vincenzo Nigro, Manuela Morleo, Victoria Paul, Careni Spencer, Alina I Esterhuizen, Tilman Polster, Alice Spano, Ins Gmez-Lozano, Abhishek Kumar, Gemma Poke, John A Phillips III, Hunter R Underhill, Gregory Gimenez, Takashi Namba, and Stephen P Robertson

American Journal of Human Genetics

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Otago University Discovers Cause of Rare Genetic Condition - Mirage News

Genetics

Genetic Analysis Guides Conservation of Endangered Bumble Bee – Entomology Today

The rusty patched bumble bee (Bombus affinis), shown here in Cherokee Regional Park in St. Paul, Minnesota, is one of nine bee species listed as endangered by the U.S. Fish and Wildlife Service, and the species only remains in a small proportion of its original range. A research team led by John Mola, Ph.D., at Colorado State University sampled rusty patched bumble bees throughout their range and examined the allele frequencies in their genomes. They found that the species occurs in three distinct clusters in the midwestern U.S., that these clusters are genetically differentiated, and that they have small population sizes. They conclude that the remaining colonies are fragile and that entomologists should be cautious about management procedures that could be disruptive to colony health. (Photo courtesy of Tamara Smith, U.S. Fish and Wildlife Service)

By John P. Roche, Ph.D.

Numerous bee species are declining in the U.S. due to pesticides, pathogens, habitat loss, and climate change. Bees are important because they pollinate 80 percent of flowering plants, including $15 billion worth of agricultural products in the U.S. each year. Genetic factors have strong effects on the viability of bee populations, so bee conservation can be strengthened by data on population genetics.

John Mola, Ph.D., assistant professor of forest and rangeland stewardship at Colorado State University, and colleagues have studied the population genetics of rusty patched bumble bees (Bombus affinis) with the goal of informing management efforts for this endangered species. They report their findings in a study published last week in the Journal of Insect Science.

Rusty patched bumble bees used to be widespread in the northeastern and midwestern U.S., but they are now gone from 7090 percent of their historical range. They are one of nine bee species classified as endangered by the U.S. Fish and Wildlife Service (USFWS).

Mola and colleagues pursued two main questions in their study: One, what is the broad population structure of rusty patched bumble bees? And, two, what are patterns of population genetic diversity and differentiation across the range of the species? The team included researchers from Colorado State University, the University of Minnesota, the University of Wisconsin, the Minnesota Zoo, the USFWS, Ohio State University, the Wisconsin Department of Natural Resources, and the USDA Agricultural Research Service, as well as two independent ecological research consultants. (For more about the project, see Rusty-patched bumblebees struggle for survival found in its genes, from the CSU Warner College of Natural Resources.)

To examine the genetic makeup of the rusty patched bumble bee populations, in 2020 and 2021 the team collected samples from the final leg segment (or tarsus) of sampled bees. They collected a total of 498 bee samples, of which, after selecting for samples that met certain screening criteria, they had 470 samples to use in the study. They extracted DNA from the samples and amplified the DNA using polymerase chain reaction (PCR). They focused on sections of DNA with repeating sequences of base pairs called microsatellite markers to examine genetic differentiation across the species range. With these genetic data, the team calculated, for each population, the genetic diversity of the samples, the degree to which individuals in populations had different alleles at the same locus (called heterozygosity), the degree of inbreeding, and the proportion of males that were diploid (males that carried two sets of DNA instead of one). Bees have a haplodiploid reproduction system in which females queens and workers are diploid (having two sets of chromosomes) and reproductive drone males are normally haploid (having one set of chromosomes).

The rusty patched bumble bee (Bombus affinis), one of nine endangered bee species in the U.S., occurs in three genetically distinct clusters in the Midwest and Appalachia, a new study shows. But low levels of genetic diversity between colonies and other underlying genetic factors suggest their populations remain fragile, researchers say. Here, study coauthor Michelle Boone, Ph.D., a graduate student at the University of Minnesota during the study and now a project manager for the U.S. National Park Service Inventory and Monitoring Division, takes genetic samples from a rusty patched bumble bee. (Photo courtesy of Tamara Smith, U.S. Fish and Wildlife Service)

The rusty patched bumble bee (Bombus affinis), one of nine endangered bee species in the U.S., occurs in three genetically distinct clusters in the Midwest and Appalachia, a new study shows. But low levels of genetic diversity between colonies and other underlying genetic factors suggest their populations remain fragile, researchers say. Here, study coauthor Michelle Boone, Ph.D., a graduate student at the University of Minnesota during the study and now a project manager for the U.S. National Park Service Inventory and Monitoring Division, takes genetic samples from a rusty patched bumble bee. (Photo courtesy of Tamara Smith, U.S. Fish and Wildlife Service)

Mola and colleagues found support for the presence of three distinct genetic clusters of rusty patched bumble bees in the U.S.: a northwestern cluster in Minnesota; a large central cluster in Wisconsin, Illinois, and Iowa; and an Appalachian cluster in West Virginia and Virginia. The clusters were isolated geographically and had small population sizes. The investigators found differences in allelic richness and in the degree of inbreeding among clusters. These clusters were found to be genetically differentiated, but it is not yet known if this differentiation was caused by the decrease in numbers in these populations or if it existed prior to the population decline.

The researchers also observed that, of 115 males sampled, 18 (~15 percent) were diploid. The presence of diploid males in bumble bee colonies suggests inbreeding. The presence of diploid males is unhealthy for bee colonies because bee populations depend on haploid males for reproduction.

The amount of genetic differentiation among the three clusters, as determined by a measure of genetic variation called the pairwise fixation index, was fairly low. This suggests that there may still be considerable gene flow among the subpopulations.

Population problems in Bombus affinis observed in the study include the presence of inbreeding and low levels of heterozygosity. Also, rusty patched bumble bee populations are so small that random environmental or genetic fluctuations could lead to local extinction of remaining colonies.

The results of this study advance our knowledge of the population genetics of rusty patched bumble bee populations. But determining the degree and significance of population size and genetic variability in a bumble bee population is complex.

One cannot just simply count the number of individuals and be confident that means there is a large and robust population, Mola says. Instead, we can use the term genetic health to suggest that the underlying genetics of the population are either in line, or not, with a population that is resilient to processes causing random perturbations. In our study, we find that the low number of genetically distinct colonies we observeas opposed to counts of individual workersand the levels of male diploidy we observei.e., inbreedingsuggest that even though counts of individual workers at a site may be high, the underlying genetics suggest those populations may be at risk.

Genetic information can help wildlife managers identify genetics-based management units in nature, help them evaluate the risk/benefit ratios of performing introductions of bees to endangered populations, and help them design optimal interventions within the limits of their budgets. Management activities aimed at bolstering declining bee populations include reintroducing individuals of a species to locales where the species formerly lived and introducing captive-reared males or females to threatened populations.

Mola and colleagues suggest that the three separate clusters of Bombus affinis may have different management needs and that entomologists should be careful about activities that could disrupt the fragile remaining colonies, including moving males or females among populations. One potential management measure they do suggest is increasing the connectivity of habitats to increase gene flow among populations.

There are limitations in being able to compare across different bumble bee studies. Different studies can collect samples in different manners, can select different genetic loci for comparison, and can score alleles in different ways, all of which make comparisons difficult. But advances in the field depend on cooperation across multiple research groups and organizations. Doing this type of work inherently requires collaboration among a large team, Mola says. The species is not necessarily easy to find, and not everyone has the appropriate training and permits to take genetic material, so no one team can do a large-scale study on their own. So, continuing the culture of data sharing, generosity, and collegiality that currently characterizes the bee-conservation community is extremely important for the success of future research and conservation efforts.

Next research steps that the team suggests include collecting comparative data on the proportion of diploid males in populations that are declining versus populations that are stable. They also suggest collecting data on similar bumble bee species that live in similar habitats.

Summing up their findings, Mola says, The results suggest that even in some of the locations that we might think of as current-day strongholds for the species, it still has a much lower number of genetically distinct colonies compared to other stable species. So, we cannot rest easy, even in these areas where we see the species year-to-year with reliability.

The decline of the rusty patched bumble bee has been precipitous. But some signs are encouraging, including considerable apparent gene flow among populations. With ongoing research and carefully planned management, we can hope that populations of the species can become more genetically robustand eventually more abundant.

John P. Roche, Ph.D., is an author, biologist, and science writer with a Ph.D. and postdoctoral fellowship in the biological sciences and a dedication to making rigorous science clear and accessible. He authors books and articles, and prepares materials for universities, scientific societies, and publishers. Professional experience includes serving as a scientist and scientific writer at Indiana University, Boston College, and the UMass Chan Medical School; serving as a visiting professor at four tier-one schools; and developing concept-based science curricula for universities and publishers.

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Genetic Analysis Guides Conservation of Endangered Bumble Bee - Entomology Today

Genetics

First insights into the genetic bottleneck characterizing early sheep husbandry in the Neolithic period – EurekAlert

image:

Excavation section in the settlement mound of Akl Hyk (Central Anatolia, Turkey). The numerous layers that formed during the millennia of settlement at the site are clearly visible.

Credit: Nadja Pllath (SNSB-SPM)

Modern Eurasian sheep predominantly belong to only two so-called genetic matrilineages inherited through the ewes. Previous research thereby assumed that genetic diversity must already have decreased rapidly in the early stages of domestication of wild sheep. Our study of a series of complete mitogenomes from the early domestication site Askl Hyk in central Anatolia, which was inhabited between 10,300 and 9,300 years ago, disproves this assumption: despite a millennium of human interference with the keeping and breeding of sheep, mitogenomic diversity remained invariably high, with five matrilineages being evidenced including one previously unknown lineage. The persistently high diversity of matrilineages observed during the 1,000 years of sheep farming was unexpected for the researchers.

"In Akl Hyk, there were both sheep raised in captivity and wild sheep hunted by the inhabitants of the site. We assume that occasionally managed flocks were supplemented by native wild sheep when necessary, e.g. to compensate for losses due to disease or stress in captivity. One should also consider that people exchanged sheep over wider areas. A possible parallel to such practice can be found in the import of cereal crops to Central Anatolia, which are native to Southeast Anatolia," says Prof. Peters, interpreting the results of the study.

The different matrilineages or haplogroups are similar to the branches of a family tree. Individuals belonging to a particular lineage show comparably little variation in their mitochondrial genomes, because descending from a common female ancestor. Today, haplogroup B predominates among sheep in Europe and haplogroup A in East Asia. Consequently, mitogenomic diversity decreased later in the domestication process or at the time when sheep farming spread beyond the original domestication region during the Neolithic, a question that had so far remained unanswered.

To address this question, the international team of researchers led by Prof. Joris Peters, State Collection of Palaeoanatomy Munich (SNSB-SPM), Prof. Ivica Medugorac, Population Genomics of Animals, LMU Munich, and Prof. Dan Bradley, Smurfit Institute for Genetics, Trinity College Dublin, investigated matrilineal affiliation and phylogenetic relationships of 629 modern and ancient sheep across Eurasia.

Comparison of Akl Hyk's results with ancient DNA signatures in archaeological sheep bones from later settlements in Anatolia and surrounding regions as well as in Europe and Middle Asia clearly illustrates that mitogenomic diversity decreased significantly in the ninth millennium before present. One result of this is the aforementioned dominance of matrilineage B in Europe. "We can now assume that this development is due to a so-called "bottleneck" that took place later in the Neolithic period, when sheep farming spread beyond the natural distribution of wild sheep following the early domestication of the species. This bottleneck likely relates to so-called founder effects, in which smaller flocks were consecutively removed from an already greatly reduced sheep population in the course of the spread of small animal husbandry on the way to Europe," Peters continued.

"Particularly fascinating are the insights gained through the integration of genetic and archaeological datasets. Together with the numerous other mosaic pieces that zooarchaeologists, archaeologists and geneticists have collected over decades, an increasingly coherent picture of human cultural adaptations since the last Ice Age now emerges. Studies like these show that animal domestication is not to be understood in terms of a cross-generational plan, but rather as a process of chance and necessity that has significantly shaped our recent cultural history and accompanies us to this day," adds Prof. Ivica Medugorac.

Animals

Ancient mitogenomes from Pre-Pottery Neolithic Central Anatolia and the effects of a Late Neo-lithic bottleneck in sheep (Ovis aries).

12-Apr-2024

The authors declare that they have no competing interests.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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First insights into the genetic bottleneck characterizing early sheep husbandry in the Neolithic period - EurekAlert

Genetics

Protein-truncating variants in BSN are associated with severe adult-onset obesity, type 2 diabetes and fatty liver disease – Nature.com

Ethics

Our research complies with all relevant ethical regulations. All studies included in this research were approved by the relevant board or committee. UK Biobank has approval from the North West Multi-centre Research Ethics Committee (REC reference 13/NW/0157) as a Research Tissue Bank (RTB) approval, and informed consent was provided by each participant. This approval means that researchers do not require separate ethical clearance and can operate under RTB approval. This RTB approval was granted initially in 2011 and is renewed every 5 years; hence, UK Biobank successfully renewed approval in 2016 and 2021. The MCPS was approved by the Mexican Ministry of Health, the Mexican National Council for Science and Technology and the University of Oxford. The PGR study was approved by the institutional review board at the Center for Non-Communicable Diseases (IRB: 00007048, IORG0005843, FWAS00014490) and all participants provided informed consent. The SCOOP cohort was approved by the Multi-regional Ethics Committee and the Cambridge Local Research Ethics Committee (MREC 97/21 and REC number 03/103). Participants (or parents for individuals <16 years old) provided written informed consent; minors provided oral consent. The INTERVAL study received ethics committee approval from the National Research Ethics Service Committee (11/EE/0538), and all participants provided informed consent before joining the study.

We used the same processing strategies as those outlined in our previous paper to analyze the WES data and perform quality control steps19. We queried WES data from 454,787 individuals in UK Biobank39, excluding those with excess heterozygosity, those with autosomal variant missingness on genotyping arrays of 5%, or those not included in the subset of phased samples as defined by Bycroft et al.13.

WES data were stored as population-level variant call format (VCF) files, aligned to GRCh38 and accessed through the UK Biobank Research Analysis Platform (RAP). In addition to the quality control measures already applied to the released data, as described by Backman et al.39, we conducted several additional quality control procedures. First, we used bcftools v1.14 norm40 to split the multiallelic sites and left-correct and normalize indels. Next, we filtered out variants that failed our quality control criteria, including those with: (1) read depth of <7; (2) genotype quality of <20; and (3) binomial test P value for alternative allele reads versus reference allele reads of 0.001 for heterozygous genotypes. For indel genotypes, we kept only variants with read depth of 10 and genotype quality of 20. Variants that failed quality control criteria were marked as missing (that is, ./.). After filtering, variants where more than 50% of the genotypes were missing were excluded from downstream analyses19.

The remaining variants underwent annotation using Ensembl Variant Effect Predictor (VEP v104)41 with the -everything flag and additional plugins for REVEL14, CADD42 and LOFTEE43. For each variant, a single Ensembl transcript was prioritized on the basis of whether the annotated transcript was protein-coding, MANE select v0.97 (ref. 44) or the VEP canonical transcript. The individual consequence for each variant was then prioritized on the basis of severity as defined by VEP. Stop-gained, splice acceptor and splice donor variants were merged into a combined PTV category, while annotations for missense and synonymous variants were adopted directly from VEP. We included only variants on autosomes and the X chromosome that were within Ensembl protein-coding transcripts and transcripts included in the UK Biobank WES assay in our downstream analysis.

Our analyses focused primarily on individuals of European genetic ancestry, and we excluded those who withdrew consent from the study, resulting in a final cohort of 419,668 individuals.

We used BOLT-LMM v2.3.6 (ref. 15) as our primary analytical tool to conduct the gene-burden test. To run BOLT-LMM, we first queried a set of genotypes with minor allele count (MAC) >100, which was derived from the genotyping arrays for the individuals with the WES data to build the null model. To accommodate BOLT-LMMs requirement for imputed genotyping data rather than per-gene carrier status, we developed dummy genotype files in which each gene was represented by a single variant. We then coded individuals with a qualifying variant within a gene as heterozygous, regardless of the total number of variants they carried in that gene. We then created dummy genotypes for the HC PTVs with MAF < 0.1% as defined by LOFTEE, missense variants with REVEL >0.5 and missense variants with REVEL >0.7. We then used BOLT-LMM to analyze phenotypes using default parameters, except for the inclusion of the lmmInfOnly flag. In addition to the dummy genotypes, we included all individual markers in the WES data to generate association test statistics for individual variants. We used age, age2, sex and the first ten principal components (PCs) as calculated by Bycroft et al.13 and the WES release batch (50k, 200k, 450k) as covariates.

To check whether there was a single variant driving the association, we performed a leave-one-out analysis for BSN and APBA1 using linear regression in R v3.6.3 by dropping the HC PTVs contained in our analysis one by one. In addition, we also checked the geographic distribution of APBA1 and BSN HC PTV carriers.

We sought replication of our findings for the four new genes in two independent predominantly non-European exome-sequenced cohorts: the MCPS and the PGR study.

MCPS is a cohort study of 159,755 adults of predominantly admixed American ancestry. Participants aged 35 years or older were recruited between 1998 and 2004 from two adjacent urban districts of Mexico City. Phenotypic data were recorded during household visits, including height, weight, and waist and hip circumferences. Disease history was self-reported at baseline, and the participants were linked to Mexican national mortality records. The cohort has been described in detail elsewhere17,18.

The PGR study has been recruiting participants aged 15100 years as cases or controls via clinical audits for specific conditions since 2005 from over 40 centers around Pakistan. Participants were recruited from clinics treating patients with cardiometabolic, inflammatory, respiratory or ophthalmological conditions. Information on lifestyle habits, medical and medication history, family history of diseases, exposure to smoking and tobacco consumption, physical activity, dietary habits, anthropometry, basic blood biochemistry and electrocardiogram traits was recorded during clinic visits. DNA, serum, plasma and whole blood samples were also collected from all study participants.

Exome sequencing data for 141,046 MCPS and 37,800 PGR participants were generated at the Regeneron Genetics Center and passed Regenerons initial quality control, which included identifying sex discordance, contamination, unresolved duplicate sequences and discordance with microarray genotype data for MCPS. Genomic DNA was subjected to paired-end 75-bp WES at Regeneron Pharmaceuticals using the IDT xGen v1 capture kit on the NovaSeq 6000 platform. Conversion of sequencing data in BCL format to FASTQ format and the assignments of paired-end sequence reads to samples were based on 10-base barcodes, using bcl2fastq v2.19.0.

These exome sequences were processed at AstraZeneca from their unaligned FASTQ state. A custom-built Amazon Web Services cloud computing platform running Illumina DRAGEN Bio-IT Platform Germline Pipeline v3.0.7 was used to align the reads to the GRCh38 genome reference and perform single-nucleotide variant (SNV) and insertion and deletion (indel) calling. SNVs and indels were annotated using SnpEff v4.3 (ref. 45) against Ensembl Build 38.92. All variants were additionally annotated with their gnomAD MAFs (gnomAD v2.1.1 mapped to GRCh38)43.

To further apply quality control to the sequence data, all MCPS and PGR exomes underwent a second screening using AstraZenecas bioinformatics pipeline, which has been described in detail previously46. Briefly, we excluded from the analysis sequences that had a VerifyBamID freemix (contamination) level of more than 4%, those for which inferred karyotypic sex did not match self-reported gender or those for which less than 94.5% of the consensus coding sequence (CCDS release 22) achieved a minimum tenfold read depth. We further removed one individual from every pair of genetic duplicates or monozygotic twins with a kinship coefficient of >0.45. Kinship coefficients were estimated from exome genotypes using the kinship function from KING v2.2.3 (ref. 47). For the MCPS, we additionally excluded sequences with an average CCDS read depth of at least 2 s.d. below the mean. After the above quality control steps, 139,603 (99.0%) MCPS and 37,727 (99.3%) PGR exomes remained.

For the MCPS, we predicted the genetic ancestry of participants using PEDDY v0.4.2 (ref. 48), with 1000 Genomes Project sequences as population ref. 49, and retained individuals with a predicted probability of admixed American ancestry of 0.95 who were within 4 s.d. of the means for the top four PCs. In the PGR study, we retained individuals with a predicted probability of South Asian ancestry of 0.95 who were within 4 s.d. of the means for the top four PCs. Following ancestry filtering, 137,059 (97.2%) MCPS and 36,280 (95.5%) PGR exomes remained.

We assessed the association of BMI and weight quantitative traits with genotype at the four proposed new genes of interest using a previously described gene-level collapsing analysis framework implementing a PTV collapsing analysis model46. We classified variants as PTVs if they had been annotated by SnpEff as follows: exon_loss_variant, frameshift_variant, start_lost, stop_gained, stop_lost, splice_acceptor_variant, splice_donor_variant, gene_fusion, bidirectional_gene_fusion, rare_amino_acid_variant and transcript_ablation.

We applied MAF filters to target rare variants: MAF <0.001 in gnomAD (overall and every population except OTH) and leave-one-out MAF <0.001 among our combined case and control test cohort. For variants to qualify, they had to also meet the following quality control filters: minimum site coverage of 10; annotation in CCDS transcripts (release 22); at least 80% alternative reads in homozygous genotypes; a percentage of alternative reads for heterozygous variants of 0.25 and 0.8; a binomial test of alternative allele proportion departure from 50% in the heterozygous state result of P >1106; GQ of 20; FS of 200 (indels) or 60 (SNVs); MQ of 40; QUAL of 30; read position rank sum score of 2; MQRS of 8; DRAGEN variant status =PASS; and test cohort carrier quality control failure of <0.5%. If the variant was observed in gnomAD exomes, we also applied the following filters: variant site achieved tenfold coverage in 25% of gnomAD exomes; variant site achieved exome z-score of 2.0; exome MQ of 30; and random forest probability that the given variant is a true SNV or indel of >0.02 and >0.01, respectively50.

For the quantitative traits and for each gene, the difference in mean between the carriers and noncarriers of PTVs was determined by fitting a linear regression model, correcting for age and sex. In addition to calculating individual statistics for the MCPS and the PGR study, we also meta-analyzed the individual study effect sizes to generate a combined replication statistic using an inverse variance-weighted fixed-effect meta-analysis using the rma.uni() function from the metafor package v3.8-1 (ref. 51) in R v3.6.3.

To test whether there was an association between pLOF variants in the BSN gene and severe early-onset obesity, we studied 927 exomes from white British participants with severe early-onset obesity recruited to the Genetics of Obesity Study (GOOS) (SCOOP cohort) and 4,057 control exomes from the INTERVAL cohort of UK blood donors. SCOOP comprises UK patients with severe obesity (BMI more than 3 s.d. above the mean for age and sex) of early onset (<10 years) recruited to the GOOS. Exome sequencing in a subset of people of white British ancestry (the SCOOP cohort) was performed as described previously52,53,54. INTERVAL comprises predominantly healthy blood donors in the UK55 (https://www.intervalstudy.org.uk).

SCOOP and INTERVAL variants were joint-called and filtered for variant-level and sample-level quality control, as previously described52. A total of 927 cases (SCOOP) and 4,057 controls (INTERVAL) passed the quality control filters53. After splitting multiallelic variants and left normalizing, we annotated variants using VEP with Ensembl v96 (GRCh37) and identified high-impact variants (predicted protein-truncating, null or splice-disrupting) in the gene BSN (transcript ENST00000296452) using VEP IMPACT=HIGH. This definition includes stop-gain variants (SNVs resulting in stop codons), frameshifts and splice donor/acceptor variants. We verified that the predicted consequences and stop codon positions were maintained in the latest minor version of the transcript (ENST00000296452.5, NM_003458.4) using VEP v110 after lifting over to GRCh38. Missense variants were detected in almost all BSN exons among SCOOP exomes (7/10 coding exons) and INTERVAL exomes (8/10 coding exons), suggesting that BSN stop-gain detection rates in cases and controls are unlikely to be driven by differential read coverage within the BSN gene.

The one PTV identified in INTERVAL (p.Trp3926*) is located at the final amino acid of the bassoon protein and is therefore unlikely to affect expression levels (note that the LOFTEE in silico stop-gain filter for low-confidence loss of function based on the 50-bp rule does not apply to the BSN gene because the termination codon is itself >55 bp from the final exonexon boundary56). After excluding this variant on the basis of low confidence for loss of function, we performed a nested gene-burden analysis on the remaining three variants: n =3 pLOF carriers in SCOOP and n =0 carriers in INTERVAL controls (OR (95% CI) = inf (1.8inf), P =0.006, Fishers exact test; adding +0.5 to each cell, OR =31). Studies in vitro are required to establish the effect of each stop-gain variant on bassoon protein expression levels and localization.

We included binary and quantitative traits made available in the June 2022 UK Biobank data release, harmonizing the phenotype data as previously described46. This resulted in 11,690 phenotypes for analysis, which are available on https://azphewas.com. On the basis of clinical relevance, we derived three additional phenotypes.

For UK Biobank phenome-wide analyses of the four putatively new genes, the same data generation and quality control processes described for the MCPS and PGR study were applied to UK Biobank exomes. Following the Regeneron and AstraZeneca quality control steps, 445,570 UK Biobank exomes remained. The phenome-wide analysis was performed in UK Biobank participants of predominantly European descent, whom we identified based on a PEDDY-derived predicted probability of European ancestry of 0.95 and were within 4 s.d. of the means for the top four PCs. On the basis of predicted ancestry pruning, 419,391 UK Biobank exomes were included in the phenome-wide analyses of the four prioritized genes.

As described previously, we assessed the association of the 11,693 phenotypes with genotypes at the four genes of interest, using a PTV collapsing analysis model46, and classifying variants as PTVs using the same SnpEff definitions as described for the MCPS and PGR analyses. For variants to qualify for inclusion in the model, we applied the same MAF and quality control filters used in the MCPS and PGR analyses, with the exception that due to the larger sample size of UK Biobank, only <0.01% of the test cohort carriers were permitted to fail quality control.

We ran association tests of APBA1 and BSN HC PTV carriers and carriers of a BMI-associated common variant (rs9843653) at the BSN locus with a list of anthropometric phenotypes available in UK Biobank using R v3.6.3 (Supplementary Table 5), including the same covariates we used in our exome-wide gene-burden tests. We acquired normalized protein expression data generated by the Olink platform from the UK Biobank RAP23,24. The detailed Olink proteomics assay, data processing and quality control were described by Sun et al.23. For the association tests of APBA1 and BSN PTV carriers and BMI-associated common variant (rs9843653) at the BSN locus carriers with expression levels for 1,463 proteins, we added age2, agesex, age2sex, Olink batch, UK Biobank center, UK Biobank genetic array, number of proteins measured and the first 20 genetic PCs as covariates, as suggested by Sun et al.23. We chose the Bonferroni-corrected P value (P <3.42105 (0.05/1,463)) as the threshold for significance.

Identified genes were queried for proximal BMI GWAS signals, using data from UK Biobank, for signals within 500 kb upstream of the genes start site to 500 kb downstream of the genes end site. Such signals were further replicated in an independent BMI GWAS9.

We also performed colocalization tests, using the approximate Bayes factor method in R v4.0.2 using the package coloc v5.1.0 and blood gene expression data from the eQTLGen study16. Genomic regions were defined as the regions 500 kb around each gene, and loci exhibiting an H4 posterior probability of >0.5 were considered to show evidence of colocalization.

Finally, we used the GWAS data to calculate gene-level common variant associations, using MAGMA v1.09 (ref. 57). To do this, we used all common but nonsynonymous (coding) variants within a given gene. Gene-level scores were further collapsed into pathway-level associations where appropriate.

To examine whether there is an interaction effect between PTV carrier status for BSN and APBA1 and the PGS, we included an interaction term between the PGS and the carrier status for BSN and APBA1 PTVs in a linear regression model adjusted for sex, age and age2, and the first 10 PCs.

The PGS was constructed for 419,581 individuals of white European ancestry who had both genotype and exome sequencing data and a BMI record in UK Biobank. We used summary statistics of BMI from Locke et al.9, which included samples not in UK Biobank. Data were downloaded from the GIANT consortium. The summary statistics included 2,113,400 single-nucleotide polymorphisms (SNPs) with at least 500,000 samples in a cohort of 322,154 participants of European ancestry. For the genotype data of UK Biobank participants, a light quality check procedure was applied, where SNPs were removed if they had a MAF of <0.1%, HardyWeinberg equilibrium P <110-6 or more than 10% missingness. In addition, SNPs that were mismatched with those in the summary statistics (with the same rsID but different chromosomes or positions) were excluded. We used the package lassosum v4.0.5 (ref. 58) in R v3.6.0 to construct the PGS. The R2 of the model including the PGS regressed on rank-based inverse normal-transformed BMI and adjusted for sex, age and age2, and the first 10 PCs as covariates was 11%.

A detailed description of the methods used in cellular work and single-cell analyses can be found in the Supplementary Note.

Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.

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Protein-truncating variants in BSN are associated with severe adult-onset obesity, type 2 diabetes and fatty liver disease - Nature.com

Genetics

Right-wing authoritarianism appears to have a genetic foundation – PsyPost

New research provides evidence that political leanings are more deeply intertwined with our genetic makeup than previously thought, specifically linked to two core ideological traits: right-wing authoritarianism and social dominance orientation. Unlike the conventional belief that our political stances are merely extensions of our personality traits, this study suggests that our views on hierarchy and social dominance have their own distinct genetic foundations. The findings have been published in the Journal of Personality.

Right-wing authoritarianism and social dominance orientation are two psychological constructs that have been extensively studied in the context of political attitudes and behaviors.

Right-wing authoritarianism is characterized by three broad attitudes: submission to authorities perceived as established and legitimate, aggression toward individuals or groups that are seen as deviant or dissenting from perceived societal norms, and adherence to conventional norms and values of the society. People high in right-wing authoritarianism tend to value order, tradition, and national unity, showing strong support for authorities that enforce these principles.

Social dominance orientation, on the other hand, reflects an individuals preference for inequality among social groups. This orientation is about the extent to which individuals desire and support hierarchical relationships between groups, believing that some groups are inherently superior to others. Those with high social dominance orientation are more likely to support policies and practices that maintain these disparities, including discrimination against perceived lower-status groups.

Previous research has established that both right-wing authoritarianism and social dominance orientation are powerful predictors of political attitudes and behaviors, independently of the Big Five personality traits. However, the extent to which these ideological traits are influenced by genetics, as opposed to environmental factors such as socialization, has been less clear.

To explore the underpinnings of political attitudes and their relationship with personality traits, researchers from the Norwegian Institute of Public Health and the University of Oslo analyzed data collected from a sample of 1,987 twins registered in the Norwegian Twin Registry, encompassing individuals born between 1945 and 1960.

The methodological core of the study relied on the classical twin design, which compares the similarities between monozygotic twins, who share virtually all their genes, and dizygotic twins, who share about half of their segregating genes. This approach allowed the researchers to distinguish genetic influences from environmental factors.

The participants completed validated measures of the Big Five personality traits (openness, conscientiousness, extraversion, agreeableness, and neuroticism), right-wing authoritarianism, and social dominance orientation. To gauge political policy attitudes, the researchers developed an index based on four specific items. These items were measured on a 7-point Likert scale ranging from 3 (against) to +3 (support) and included attitudes towards deporting the Roma, reducing aid for developing countries, accepting more asylum seekers (reversed), and implementing strict immigration control.

The researchers found that the covariation between ideological traits and policy attitudes related to national resources and immigration was predominantly explained by genetic factors. This genetic overlap implies that the propensity towards certain political views, especially those concerning hierarchy and authority, can be significantly influenced by ones genetic makeup.

In contrast, the Big Five personality traits, while influential in shaping individuals general attitudes and behaviors, have a comparatively lesser genetic correlation with specific political policy attitudes. This indicates that the Big Five might play a more indirect role in political ideology, perhaps by influencing broader worldview or cognitive style, rather than specific political beliefs.

Furthermore, the study highlighted a significant genetic correlation between right-wing authoritarianism and social dominance orientation themselves, suggesting a common genetic architecture underlies these traits. This is an intriguing finding as it supports the notion that these orientations might not be entirely distinct in their genetic roots, despite differing in their social and psychological manifestations.

Right-wing authoritarianism and social dominance orientation, therefore, appear to form a genetically influenced framework for understanding hierarchy and group dynamics, which in turn shapes individuals political attitudes.

Another notable result is the lack of significant shared environmental effects for most traits, including social dominance orientation and the Big Five personality traits, suggesting that shared family environment and upbringing do not play a major role in developing these ideological orientations. However, a modest shared environmental effect was observed for right-wing authoritarianism, indicating that some aspects of authoritarian attitudes might be influenced by environmental factors common to twins, such as family values or cultural context.

These findings challenge some traditional views in political and social psychology, particularly those that emphasize the role of upbringing and social environment in shaping political ideology. Instead, the results support a more nuanced view that acknowledges a significant genetic component to political attitudes, alongside and sometimes even above personality traits traditionally linked to political orientation.

Our results suggest that the two core ideological traits of [right-wing authoritarianism] and [social dominance orientation] have a much higher (genetic and phenotypic) covariation with political policy attitudes than do Big Five personality traits, the researchers concluded.

The covariation of such ideological traits with policy attitudes is best explained by genetic overlap as opposed to common socialization. These findings challenge key influential theories in social and political psychology and suggest instead that hierarchy-related traits are not simply epiphenomena or downstream consequences of standard personality traits, but instead might form a dedicated and heritable package for navigating intergroup struggles over territory and resources.

But the study, like all research, includes some limitations. For one, it relies on data from a relatively homogeneous population middle-aged adults from Norway which might not represent the global diversity in political attitudes. Future research could expand on these findings by exploring other populations.

The study, The genetic underpinnings of right-wing authoritarianism and social dominance orientation explain political attitudes beyond Big Five personality, was authored by Thomas Haarklau Kleppesto, Nikolai Olavi Czajkowski, Jennifer Sheehy-Skeffington, Olav Vassend, Espen Roysamb, Nikolai Haahjem Eftedal, Jonas R. Kunst, Eivind Ystrom, and Lotte Thomsen.

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Right-wing authoritarianism appears to have a genetic foundation - PsyPost

Genetics

UC Irvine-led research team builds first tandem repeat expansions genetic reference maps – UCI News

Irvine, Calif., April 5, 2024 A research team led by the University of California, Irvine has built the first genetic reference maps for short lengths of DNA repeated multiple times which are known to cause more than 50 lethal human diseases, including amyotrophic lateral sclerosis, Huntingtons disease and multiple cancers.

The UC Irvine Tandem Genome Aggregation Database enables researchers to study how these mutations called tandem repeat expansions are connected to diseases, to better understand health disparities and to improve clinical diagnostics.

The study, published online today in the journal Cell, introduces the UC Irvine TR-gnomAD, which addresses a critical gap in current biobank genome sequencing efforts. Although TR expansions constitute about 6 percent of our genome and substantially contribute to complex congenial conditions, scientific understanding of them remains limited.

This groundbreaking project positions UC Irvine as a leader in human and medical genetics by addressing the critical gap in the ability to interpret TR expansions in individuals with genetic disorders, said Wei Li, the Grace B. Bell Chair and professor of bioinformatics and co-corresponding author. The TR-gnomAD advances our ability to determine how certain diseases might affect diverse groups of people based on variations in these mutations among ancestries. Genetic consulting companies can then develop products to interpret this information and accurately report how certain traits might be linked to different groups of people and diseases.

To build the database, the team utilized two software tools to analyze the genomic data of 338,963 participants across 11 sub-populations. Of the .91 million TRs identified, .86 million were of high enough quality to be retained for further study. It was also discovered that 30.5 percent of them had at least two common alternative forms of a gene caused by a mutation located in the same place on a chromosome.

Although weve successfully genotyped a substantial number of TRs, that is still just a fraction of the total number in the human genome, Li said. Our next steps will be to prioritize the integration of a greater number of high-quality TR and include more underrepresented ancestries, such as Australian, Pacific Islander and Mongolian, as we move closer to realizing personalized precision medicine.

UC Irvine team members involved in the research included co-corresponding author and research assistant professor Ya Cui; Wenbin Ye, postdoctoral scholar; Jason Sheng Li, biological chemistry graduate student; and Eric Vilain, professor of pediatrics and the director of the Institute for Clinical andTranslational Science. Also participating were Jingi Jessica Le, UCLA biostatistics professor, and Dr. Tamer Sallam, vice chair and associate professor at the UCLA David Geffen School of Medicine.

UC Irvines Brilliant Future campaign: Publicly launched on Oct. 4, 2019, the Brilliant Future campaign aims to raise awareness and support for UC Irvine. By engaging 75,000 alumni and garnering $2 billion in philanthropic investment, UC Irvine seeks to reach new heights of excellence instudent success, health and wellness, research and more. The School of Medicine plays a vital role in the success of the campaign. Learn more by visiting https://brilliantfuture.uci.edu/uci-school-of-medicine.

About the University of California, Irvine:Founded in 1965, UC Irvine is a member of the prestigious Association of American Universities and is ranked among the nations top 10 public universities byU.S. News & World Report. The campus has produced five Nobel laureates and is known for its academic achievement, premier research, innovation and anteater mascot. Led by Chancellor Howard Gillman, UC Irvine has more than 36,000 students and offers 224 degree programs. Its located in one of the worlds safest and most economically vibrant communities and is Orange Countys second-largest employer, contributing $7 billion annually to the local economy and $8 billion statewide.For more on UC Irvine, visitwww.uci.edu.

Media access: Radio programs/stations may, for a fee, use an on-campus ISDN line to interview UC Irvine faculty and experts, subject to availability and university approval. For more UC Irvine news, visit news.uci.edu. Additional resources for journalists may be found at https://news.uci.edu/media-resources.

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UC Irvine-led research team builds first tandem repeat expansions genetic reference maps - UCI News

Genetics

A Deep Dive Into the Genetics of Alcohol Consumption – University of California San Diego

But the paper notes individuals with the alcohol-protective alleles also had worse health outcomes in certain areas: more lifetime tobacco use, more emotional eating, more Graves disease and hyperthyroidism. Individuals with the alcohol-protective alleles also reported totally unexpected differences, such as more malaria, more myopia and several cancers, particularly more skin cancer and lung cancer, and more migraine with aura.

Sanchez-Roige acknowledged that there is a chicken-and-egg aspect to their findings. For example: Cardiovascular disease is just one of a number of maladies known to be associated with alcohol consumption. So is alcohol consumption leading to these conditions? she asks. Palmer finishes the thought: Or do these genetic differences influence traits like malaria and skin cancer in a manner that is independent of alcohol consumption?

Sanchez-Roige said that such broad, hypothesis-free studies are only possible if researchers have access to very large sets of data. Many datasets, including the one used in the study, rely heavily on individuals with European ancestry.

It is important to include individuals from different ancestral backgrounds in genetic studies because it provides a more complete understanding of the genetic basis of alcohol behaviors and other conditions, all of which contributes to a more inclusive and accurate understanding of human health, she said. The study of only one group of genetically similar individuals (for example, individuals of shared European ancestry) could worsen health disparities by aiding discoveries that will disproportionately benefit only that population.

She said their study opens numerous doors for future research, chasing down possible connections between the alcohol-protective alleles and conditions that have no apparent connection with alcohol consumption.

Understanding the underlying mechanisms of these effects could have implications for treatments and preventative medicine, Sanchez-Roige noted.

Co-authors on the paper from the University of California San Diego School of Medicine Department of Psychiatry are Mariela V. Jennings, Natasia S. Courchesne-Krak, Renata B. Cupertino and Sevim B. Bianchi. Sandra Sanchez-Roige is also associated with the Department of Medicine, Division of Genetic Medicine, Vanderbilt University.

Other co-authors are: Jos Jaime Martnez-Magaa, Department of Psychiatry, Division of Human Genetics, Yale University School of Medicine; Laura Vilar-Rib, Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall dHebron Research Institute, Universitat Autnoma de Barcelona, Barcelona, Spain; Alexander S. Hatoum, Department of Psychology & Brain Sciences, Washington University in St. Louis; Elizabeth G. Atkinson, Department of Molecular and Human Genetics, Baylor College of Medicine; Paola Giusti-Rodriguez, Department of Psychiatry, University of Florida College of Medicine; Janitza L. Montalvo-Ortiz, Department of Psychiatry, Division of Human Genetics, Yale University School of Medicine, National Center of Posttraumatic Stress Disorder, VA CT Healthcare Center; Joel Gelernter, VA CT Healthcare Center, Department of Psychiatry, West Haven CT; and Departments of Psychiatry, Genetics & Neuroscience, Yale Univ. School of Medicine; Mara Soler Artigas, Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall dHebron Research Institute, Universitat Autnoma de Barcelona, Barcelona, Spain; Department of Mental Health, Hospital Universitari Vall dHebron, Barcelona; Biomedical Network Research Centre on Mental Health (CIBERSAM), Madrid; and Department of Genetics, Microbiology, and Statistics, Faculty of Biology, Universitat de Barcelona; Howard J. Edenberg, Department of Biochemistry and Molecular Biology, Indiana University School of Medicine; and the 23andMe Inc. Research Team, including Sarah L. Elson and Pierre Fontanillas.

The study was funded, in part, by Tobacco-Related Disease Research Program grants T32IR5226 and 28IR-0070, National Institute of Health (NIH) National Institute of Drug Abuse (NIDA) DP1DA054394, and NIH National Institute of Mental Health (NIMH) R25MH081482.

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A Deep Dive Into the Genetics of Alcohol Consumption - University of California San Diego

Genetics

Untold story of bird evolution revealed through genetics – Earth.com

The cataclysmic impact of a giant meteor around 65 million years ago brought an end to the reign of the majority of dinosaur species, leaving behind a void in which birds, the direct descendants of dinosaurs, emerged as thriving survivors.

This event marks a critical junction in the evolution of birds, which have since exploded into a diverse group of approximately 10,000 species today.

Scientists have long struggled to piece together a comprehensive family tree of birds to understand their evolutionary journey across millennia.

The advent of affordable DNA sequencing technologies promised a resolution to this complex puzzle, simplifying the classification process that has bewildered researchers for centuries, much like it has facilitated the understanding of lineage and relationships across a multitude of other species.

However, the avian world was not without its enigmas. Recent scientific endeavors have found that an event concurrent with the dinosaurs demise 65 million years ago had obscured the true lineage of birds.

This discovery emerged from a pair of groundbreaking research papers released on April 1, which identified a segment of one chromosome that remained in stasis, resisting the natural blending with adjacent DNA regions over the course of millions of years.

This peculiar fragment, representing a mere two percent of the entire bird genome, previously led scientists to believe that the avian family tree could be broadly divided into two major groups, with species such as flamingos and doves considered closely related evolutionary kin.

The discovery of a more precise family tree, which takes into account the deceptive nature of this genome segment, now proposes four primary avian groups and places flamingos and doves in more distant branches of the evolutionary lineage.

My lab has been chipping away at this problem of bird evolution for longer than I want to think about, said senior author Edward Braun, a professor of biology at the University of Florida. We had no idea there would be a big chunk of the genome that behaved unusually. We kind of stumbled onto it.

Decades ago, Braun and his team embarked on a journey to construct a family tree for the Neoaves, which encompasses the majority of existing bird species.

Initial analyses based on the genomes of 48 species led to the classification of the Neoaves into two overarching categories, segregating doves and flamingos into one group, with all other species in the opposing group.

A subsequent analysis involving 363 species, however, produced a divergent family tree that separated doves and flamingos into distinct categories.

Confronted with two conflicting interpretations of the avian family tree, the researchers delved deeper into the genetic data in search of clues that could clarify which version was correct.

When we looked at the individual genes and what tree they supported, all of a sudden it popped out that all the genes that support the older tree, theyre all in one spot. Thats what started the whole thing, Braun explained.

Further investigations revealed that a specific section of the bird chromosome had not undergone the expected genetic mixing through the process of recombination a fundamental mechanism in sexual reproduction that ensures genetic diversity within a species.

This suppression of recombination in a critical genome segment coinciding with the period of dinosaur extinction had caused flamingos and doves to appear more closely related than they truly are when considering the entirety of the genome.

The discovery of this anomalous genomic region, capable of misleading evolutionary analysis yet detectable more than 60 million years later, is a proof of the complexity of bird evolution and the challenges inherent in unraveling the true history of these avian descendants of dinosaurs.

Braun highlighted the potential for similar mysteries to exist within the genomes of other organisms, as yet undiscovered due to the lack of extensive genetic sequencing efforts.

We discovered this misleading region in birds because we put a lot of energy into sequencing birds genomes. I think there are cases like this out there for other species that are just not known right now, Braun concluded.

The study is published in the journal Proceedings of the National Academy of Science.

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Untold story of bird evolution revealed through genetics - Earth.com

Genetics

Genetic Test for Opioid Addiction Risk Should Be Withdrawn, Experts Tell FDA – Medpage Today

A group of 31 physicians and researchers called on the FDA to reverse its decision about AvertD, a test that uses DNA to identify whether adults may have an elevated risk of developing opioid use disorder (OUD).

In a letter to FDA Commissioner Robert Califf, MD, experts in genetics, addiction, psychiatry, public health, and device regulation asked the agency to revoke its recent approval of AvertD, based on research that doesn't support the methodology used by the test's sponsor.

The group also sent a letter to Centers for Medicare & Medicaid Services (CMS) Administrator Chiquita Brooks-LaSure asking CMS to deny coverage of AvertD.

The FDA approved AvertD in December 2023. The prescription-only genetic test from SOLVD Health is expected to be on the market soon.

AvertD detects the presence of 15 single nucleotide polymorphisms (SNPs) to help identify people who may have an increased risk of OUD. It's intended to be used in combination with clinical evaluations and patient assessments when oral prescription opioids are being considered to treat acute pain.

The major risks associated with AvertD are false-negative and false-positive results, the FDA said. Before the agency approved it, an FDA advisory committee voted strongly against an earlier version of AvertD, with false-negative and false-positive test results being a primary concern.

"The FDA seems to believe the test isn't a very good test but that it's better than nothing. They've got it wrong," said Andrew Kolodny, MD, an opioid policy expert at Brandeis University in Massachusetts, who signed the letters to the FDA and CMS.

"The problem isn't that the test has weak specificity and sensitivity," Kolodny told MedPage Today. "The problem is that it doesn't work at all. It's 100% bogus."

The AvertD test will harm people, Kolodny emphasized. "Patients who test negative, and their clinicians, will be left with a false sense of security, which can result in overuse of opioids and addiction," he said.

"Patients who test positive will be falsely branded as prone to a highly stigmatized condition," he continued. "And they may become fearful of taking opioids, even in situations where use is beneficial."

Genetic tests for opioid addiction have a checkered history. The FDA approval of AvertD last year was an industry first.

Like many genetic tests, confounding is part of the problem, Kolodny and colleagues said. An independent evaluation using methodology like the one used to test AvertD found that the algorithm gave the appearance of predicting genetic risk but was not a true measure of genetic risk, they noted.

"With proper controls for ancestry, genetic predictors from the 15 variants used in AvertD did not predict risk of OUD any better than chance," they said in their letters to the FDA and CMS.

SOLVD Health said it was aware of the letters to FDA and CMS and is reviewing them.

"We believe the FDA approval of AvertD represents a significant step forward in helping clinicians and patients have informed discussions about opioid-sparing techniques or alternative pain management options, if medically appropriate," the company said in an email to MedPage Today.

"Consistent with regulatory guidelines and standards, AvertD was clinically validated through a blinded, multicenter study evaluating participants at least 1 year after their initial exposure to prescription oral opioids," SOLVD noted. "In the hands of physicians, the test results can be a critical tool to help combat opioid use disorder."

The company also said it is conducting prospective post-market studies to further evaluate the test's performance in real-world settings.

Judy George covers neurology and neuroscience news for MedPage Today, writing about brain aging, Alzheimers, dementia, MS, rare diseases, epilepsy, autism, headache, stroke, Parkinsons, ALS, concussion, CTE, sleep, pain, and more. Follow

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Genetic Test for Opioid Addiction Risk Should Be Withdrawn, Experts Tell FDA - Medpage Today