GWAS including 82,707 subjects identifies functional coding variant in OPRM1 gene associated with opioid use disorder

AbstractOne way to address the current crisis in opioid use is to improve our understanding of the biological mechanisms of opioid use disorder (OUD). We completed a primary GWAS of electronic health record-defined OUD in European-ancestry participants in the Million Veteran Program (MVP) sample, which included 8,529 affected subjects and 71,200 opioid-exposed controls. In the MVP alone, there were no genome-wide significant (GWS) associations. We then subjected the MVP and additional OUD GWAS results from the Yale-Penn and SAGE samples to meta-analysis (in total, 10,544 OUD cases and 72,163 opioid-exposed controls). A functional coding variant (rs1799971, encoding Asn40Asp) in OPRM1 (mu opioid receptor gene, the main biological target for opioid drugs) reached GWS (p=1.51×10−8); then replicated in two independent samples (each at p<0.05). The final meta-analyzed p-value for this variant in all samples was 7.81×10−10. SNP-based heritability of OUD was 11.3%. OUD was genetically correlated with 83 traits, including multiple substance use traits, psychiatric illnesses, cognitive performance, and others. Mendelian Randomization revealed possible causal effects on OUD risk from tobacco smoking, major depression, neuroticism, and cognitive performance. Despite the inclusion of data from the MVP, discovery of a significant association depended on including other purpose-collected samples as well. Recruitment of additional opioid dependent subjects for future studies – especially of non-European ancestry – is a crucial next step.

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Cross-ancestry meta-analysis of opioid use disorder uncovers novel loci with predominant effects on brain

10.1101/2021.12.13.21267480 ◽

2021 ◽

Author(s):

Rachel L Kember ◽

Rachel A. Vickers-Smith ◽

Heng Xu ◽

Sylvanus Toikumo ◽

Maria Niarchou ◽

...

Keyword(s):

Association Studies ◽

Meta Analysis ◽

Genetic Correlations ◽

Opioid Use Disorder ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Opioid Use ◽

Opioid Prescription ◽

Genome Wide ◽

The Cross

Despite an estimated twin heritability of ~50%, genome-wide association studies (GWAS) of opioid use disorder (OUD) have revealed few genome-wide significant (GWS) loci, with replicated findings only in European-ancestry individuals. To identify novel loci, including those in non-European ancestries, and improve our understanding of the biology of OUD, we conducted a cross-ancestry meta-analysis using the Million Veteran Program (MVP). OUD cases in MVP had at least 1 International Classification of Diseases (ICD)-9 or ICD-10 code for opioid abuse or dependence (N=31,473). Opioid-exposed controls (N=394,471) had one or more outpatient opioid prescription fills. We conducted GWAS for each major ancestral group in MVP: African Americans (AAs; N=88,498), European Americans (EAs; N=302,585), and Hispanic Americans (HAs; N=34,861), followed by a cross-ancestry meta-analysis. Ten loci were GWS in the cross-ancestry meta-analysis, 8 of them novel. In addition to the known coding variant rs1799971 in OPRM1, which was the lead SNP genome-wide (p=6.78x10-10), and a recently reported exonic variant in FURIN, we identified intronic variants in RABEPK, FBXW4, NCAM1, and KCNN1. Ancestry-specific analyses identified an additional novel locus for each of the 3 ancestry groups. A supplementary meta-analysis within EAs that included MVP and other samples identified a locus in TSNARE1, which was also GWS in the cross-ancestry meta-analysis of all datasets. Gene-based association analyses identified 1 gene in AAs (CHRM2) and 3 in EAs (OPRM1, DRD2, and FTO). Significant genetic correlations (rg's) were identified for 127 traits, including positive correlations with schizophrenia, problematic alcohol use, and major depressive disorder. The most significantly enriched cell type group was the central nervous system with gene-expression enrichment identified in brain regions previously associated with substance use disorders. With a case sample 50% larger than that of the previous largest GWAS, we identified 14 loci for OUD, including 12 novel loci, some of which were ancestry specific. These findings increase our understanding of the biological pathways involved in OUD, which can inform preventive, diagnostic, and therapeutic efforts and thereby help to address the opioid epidemic.

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Cross-ancestry meta-analysis of opioid use disorder uncovers novel loci with predominant effects on brain

10.21203/rs.3.rs-1167873/v1 ◽

2021 ◽

Author(s):

Rachel Kember ◽

Rachel Vickers-Smith ◽

Heng Xu ◽

Sylvanus Toikumo ◽

Maria Niarchou ◽

...

Keyword(s):

Association Studies ◽

Meta Analysis ◽

Genetic Correlations ◽

Opioid Use Disorder ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Opioid Use ◽

Opioid Prescription ◽

Genome Wide ◽

The Cross

Abstract Despite an estimated twin heritability of ~50%, genome-wide association studies (GWAS) of opioid use disorder (OUD) have revealed few genome-wide significant (GWS) loci, with replicated findings only in European-ancestry individuals. To identify novel loci, including those in non-European ancestries, and improve our understanding of the biology of OUD, we conducted a cross-ancestry meta-analysis using the Million Veteran Program (MVP). OUD cases in MVP had at least 1 International Classification of Diseases (ICD)-9 or ICD-10 code for opioid abuse or dependence (N=31,473). Opioid-exposed controls (N=394,471) had one or more outpatient opioid prescription fills. We conducted GWAS for each major ancestral group in MVP: African Americans (AAs; N=88,498), European Americans (EAs; N=302,585), and Hispanic Americans (HAs; N=34,861), followed by a cross-ancestry meta-analysis. Ten loci were GWS in the cross-ancestry meta-analysis, 8 of them novel. In addition to the known coding variant rs1799971 in OPRM1, which was the lead SNP genome-wide (p=6.78x10−10), and a recently reported exonic variant in FURIN, we identified intronic variants in RABEPK, FBXW4, NCAM1, and KCNN1. Ancestry-specific analyses identified an additional novel locus for each of the 3 ancestry groups. A supplementary meta-analysis within EAs that included MVP and other samples identified a locus in TSNARE1, which was also GWS in the cross-ancestry meta-analysis of all datasets. Gene-based association analyses identified 1 gene in AAs (CHRM2) and 3 in EAs (OPRM1, DRD2, and FTO). Significant genetic correlations (rg’s) were identified for 127 traits, including positive correlations with schizophrenia, problematic alcohol use, and major depressive disorder. The most significantly enriched cell type group was the central nervous system with gene-expression enrichment identified in brain regions previously associated with substance use disorders. With a case sample 50% larger than that of the previous largest GWAS, we identified 14 loci for OUD, including 12 novel loci, some of which were ancestry specific. These findings increase our understanding of the biological pathways involved in OUD, which can inform preventive, diagnostic, and therapeutic efforts and thereby help to address the opioid epidemic.

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Prevalence of childhood maltreatment among people with opioid use disorder: A systematic review and meta-analysis

Drug and Alcohol Dependence ◽

10.1016/j.drugalcdep.2020.108459 ◽

2021 ◽

Vol 219 ◽

pp. 108459

Author(s):

Thomas Santo ◽

Gabrielle Campbell ◽

Natasa Gisev ◽

Lucy Thi Tran ◽

Samantha Colledge ◽

...

Keyword(s):

Systematic Review ◽

Childhood Maltreatment ◽

Meta Analysis ◽

Opioid Use Disorder ◽

Opioid Use

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Opioid Use Disorder Comorbidity in Individuals With Schizophrenia-Spectrum Disorders: A Systematic Review and Meta-Analysis

The Canadian Journal of Addiction ◽

10.1097/cxa.0000000000000128 ◽

2021 ◽

Vol 12 (4) ◽

pp. 26-37

Author(s):

Marlon Danilewitz ◽

Anees Bahji

Keyword(s):

Systematic Review ◽

Meta Analysis ◽

Opioid Use Disorder ◽

Schizophrenia Spectrum Disorders ◽

Opioid Use ◽

Schizophrenia Spectrum ◽

Spectrum Disorders

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1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function

Scientific Reports ◽

10.1038/srep45040 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 51

Author(s):

Mathias Gorski ◽

Peter J. van der Most ◽

Alexander Teumer ◽

Audrey Y. Chu ◽

Man Li ◽

...

Keyword(s):

Kidney Function ◽

Kidney Development ◽

Association Studies ◽

Meta Analysis ◽

European Ancestry ◽

P Value ◽

Genome Wide Association Studies ◽

1000 Genomes ◽

Gene Sets ◽

Project Promise

Abstract HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10−8 previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples.

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Abstract 16160: Common Autosomal Variants are Associated With Bicuspid Aortic Valve in Turner Syndrome

Circulation ◽

10.1161/circ.130.suppl_2.16160 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Siddharth Prakash ◽

Michael Silberbach ◽

Federico Asch ◽

Giuseppe Limongelli ◽

Hector Michelena ◽

...

Keyword(s):

Turner Syndrome ◽

Meta Analysis ◽

Copy Number Variants ◽

European Ancestry ◽

P Value ◽

Scaling Analysis ◽

Aortic Valves ◽

Genome Wide ◽

Independent Review ◽

Tests Of Association

Introduction: The prevalence of bicuspid aortic valves (BAV) is enriched thirty-fold in women with Turner Syndrome (TS) in comparison with the general population. Hypothesis: Common autosomal variants influence the development of BAV in TS women, who may be uniquely sensitized to these variants by the loss of one X chromosome. We sought to identify autosomal BAV susceptibility genes in a cohort of TS women (average age 30 years, 38% BAV, 18% coarctation). Methods: A total of 106 TS women of European ancestry with BAV and 173 TS women with tricuspid aortic valves were genotyped on Illumina Omni-Express arrays. Valve phenotypes were determined by independent review of echocardiograms from the enrolling sites. Tests of association were performed using logistic regression without adjustment for covariates and were summarized in a meta-analysis. Results: Xp dosage was inversely and quantitatively associated with BAV status (P=0.02). Large, recurrent copy number variants in 1p36.13, 3q29, 8p23.1 and 9p24.3 were significantly enriched in BAV cases. After exclusion of 26 outlier samples in multidimensional scaling analysis, there was no significant genomic inflation (lambda= 1.02). The strongest genome-wide association signals were observed in 1p36.23, 3q23, 12q21.2, 18q21 and 22q13.31, and did not overlap with previously reported loci for BAV. A total of 13 SNPs in 18q21 were positively associated with BAV (OR=2.5-4.3) with a minimum P value of 1x10-7. Replication of these regions in independent groups of cases is ongoing. Conclusion: Our results demonstrate that autosomal variants with large magnitudes of effect contribute to BAV in TS women, confirming our hypothesis, and provide evidence for gene-gene interactions in BAV formation.

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