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Bi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in >1.2 million individuals highlight new therapeutic directions Levey DF, Stein MB, Wendt FR, Pathak GA, Zhou H, Aslan M, Quaden R, Harrington KM, Nuñez YZ, Overstreet C, Radhakrishnan K, Sanacora G, McIntosh AM, Shi J, Shringarpure SS, Concato J, Polimanti R, Gelernter J. Bi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in >1.2 million individuals highlight new therapeutic directions Nature Neuroscience 2021, 24: 954-963. PMID: 34045744, PMCID: PMC8404304, DOI: 10.1038/s41593-021-00860-2.

Major depressive disorder is the most common neuropsychiatric disorder, affecting 11% of veterans. Here we report results of a large meta-analysis of depression using data from the Million Veteran Program, 23andMe, UK Biobank and FinnGen, including individuals of European ancestry (n = 1,154,267; 340,591 cases) and African ancestry (n = 59,600; 25,843 cases). Transcriptome-wide association study analyses revealed significant associations with expression of NEGR1 in the hypothalamus and DRD2 in the nucleus accumbens, among others. We fine-mapped 178 genomic risk loci, and we identified likely pathogenicity in these variants and overlapping gene expression for 17 genes from our transcriptome-wide association study, including TRAF3. Finally, we were able to show substantial replications of our findings in a large independent cohort (n = 1,342,778) provided by 23andMe. This study sheds light on the genetic architecture of depression and provides new insight into the interrelatedness of complex psychiatric traits.

Deak, J. D., Zhou, H., Galimberti, M., Levey, D. F., Wendt, F. R., Sanchez-Roige, S., Hatoum, A. S., Johnson, E. C., Nunez, Y. Z., Demontis, D., Børglum, A. D., Rajagopal, V. M., Jennings, M. V., Kember, R. L., Justice, A. C., Edenberg, H. J., Agrawal, A., Polimanti, R., Kranzler, H. R., & Gelernter, J. (2022). Genome-wide association study in individuals of European and African ancestry and multi-trait analysis of opioid use disorder identifies 19 independent genome-wide significant risk loci. Molecular Psychiatry. https://doi.org/10.1038/s41380-022-01709-1

Despite the large toll of opioid use disorder (OUD), genome-wide association studies (GWAS) of OUD to date have yielded few susceptibility loci. We performed a large-scale GWAS of OUD in individuals of European (EUR) and African (AFR) ancestry, optimizing genetic informativeness by performing MTAG (Multi-trait analysis of GWAS) with genetically correlated substance use disorders (SUDs). Meta-analysis included seven cohorts: the Million Veteran Program, Psychiatric Genomics Consortium, iPSYCH, FinnGen, Partners Biobank, BioVU, and Yale-Penn 3, resulting in a total N = 639,063 (Ncases = 20,686;Neffective = 77,026) across ancestries. OUD cases were defined as having a lifetime OUD diagnosis, and controls as anyone not known to meet OUD criteria. We estimated SNP-heritability (h2SNP) and genetic correlations (rg). Based on genetic correlation, we performed MTAG on OUD, alcohol use disorder (AUD), and cannabis use disorder (CanUD). A leave-one-out polygenic risk score (PRS) analysis was performed to compare OUD and OUD-MTAG PRS as predictors of OUD case status in Yale-Penn 3. The EUR meta-analysis identified three genome-wide significant (GWS; p ≤ 5 × 10−8) lead SNPs—one at FURIN (rs11372849; p = 9.54 × 10−10) and two OPRM1 variants (rs1799971, p = 4.92 × 10−09; rs79704991, p = 1.11 × 10−08; r2 = 0.02). Rs1799971 (p = 4.91 × 10−08) and another OPRM1 variant (rs9478500; p = 1.95 × 10−08; r2 = 0.03) were identified in the cross-ancestry meta-analysis. Estimated h2SNP was 12.75%, with strong rg with CanUD (rg = 0.82; p = 1.14 × 10−47) and AUD (rg = 0.77; p = 6.36 × 10−78). The OUD-MTAG resulted in a GWAS Nequivalent = 128,748 and 18 independent GWS loci, some mapping to genes or gene regions that have previously been associated with psychiatric or addiction phenotypes. The OUD-MTAG PRS accounted for 3.81% of OUD variance (beta = 0.61;s.e. = 0.066; p = 2.00 × 10−16) compared to 2.41% (beta = 0.45; s.e. = 0.058; p = 2.90 × 10−13) explained by the OUD PRS. The current study identified OUD variant associations at OPRM1, single variant associations with FURIN, and 18 GWS associations in the OUD-MTAG. The genetic architecture of OUD is likely influenced by both OUD-specific loci and loci shared across SUDs.

Isabelle Austin-Zimmerman, Daniel F. Levey, Olga Giannakopoulou, Joseph D. Deak, Marco Galimberti, Keyrun Adhikari, Hang Zhou, Spiros Denaxas, Haritz Irizar, Karoline Kuchenbaecker, Andrew McQuillin, the Million Veteran Program, John Concato, Daniel J. Buysse, J. Michael Gaziano, Daniel J. Gottlieb, Renato Polimanti, Murray B. Stein, Elvira Bramon & Joel Gelernter

Sleep duration has been linked to a wide range of negative health outcomes and to reduced life expectancy. We present genome-wide association studies of short ( ≤ 5 h) and long ( ≥ 10 h) sleep duration in adults of European (N = 445,966), African (N = 27,785), East Asian (N = 3141), and admixed-American (N = 16,250) ancestry from UK Biobank and the Million Veteran Programme. In a cross-population meta-analysis, we identify 84 independent loci for short sleep and 1 for long sleep. We estimate SNP-based heritability for both sleep traits in each ancestry based on population derived linkage disequilibrium (LD) scores using cov-LDSC. We identify positive genetic correlation between short and long sleep traits (rg = 0.16 ± 0.04; p = 0.0002), as well as similar patterns of genetic correlation with other psychiatric and cardiometabolic phenotypes. Mendelian randomisation reveals a directional causal relationship between short sleep and depression, and a bidirectional causal relationship between long sleep and depression.

Daniel F. Levey, Marco Galimberti, Joseph D. Deak, Frank R. Wendt, Arjun Bhattacharya, Dora Koller, Kelly M. Harrington, Rachel Quaden, Emma C. Johnson, Priya Gupta, Mahantesh Biradar, Max Lam, Megan Cooke, Veera M. Rajagopal, Stefany L. L. Empke, Hang Zhou, Yaira Z. Nunez, Henry R. Kranzler, Howard J. Edenberg, Arpana Agrawal, Jordan W. Smoller, Todd Lencz, David M. Hougaard, Anders D. Børglum, Veterans Affairs Million Veteran Program, Joel Gelernter

In this study, we conducted meta-analyses of alcohol use disorder (AUD) and problematic alcohol use (PAU, a proxy to AUD) in multiple ancestries. Summary data can be downloaded in the following links. Please contact us if there is any problem (hang.zhou@yale.edu)