Alcohol consumption level and alcohol use disorder (AUD) diagnosis are moderately heritable traits. We conduct genome-wide association studies of these traits using longitudinal Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) scores and AUD diagnoses in a multi-ancestry Million Veteran Program sample ( N = 274,424). We identify 18 genome-wide significant loci: 5 associated with both traits, 8 associated with AUDIT-C only, and 5 associated with AUD diagnosis only. Polygenic Risk Scores (PRS) for both traits are associated with alcohol-related disorders in two independent samples. Although a significant genetic correlation reflects the overlap between the traits, genetic correlations for 188 non-alcohol-related traits differ significantly for the two traits, as do the phenotypes associated with the traits’ PRS. Cell type group partitioning heritability enrichment analyses also differentiate the two traits. We conclude that, although heavy drinking is a key risk factor for AUD, it is not a sufficient cause of the disorder.

Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest GWAS to date of DSM-IV diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case/control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, N = 46,568; African; N = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; p = 9.8E-13) and African ancestries (rs2066702; p = 2.2E-9). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, ADHD, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and non-pathological drinking behaviors.

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5–20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson’s disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.

Problematic alcohol use (PAU) is a leading cause of death and disability worldwide. Although genome-wide association studies (GWASs) have identified PAU risk genes, the genetic architecture of this trait is not fully understood. We conducted a proxy-phenotype meta-analysis of PAU combining alcohol use disorder and problematic drinking in 435,563 European-ancestry individuals. We identified 29 independent risk variants, 19 of them novel. PAU was genetically correlated with 138 phenotypes, including substance use and psychiatric traits. Phenome-wide polygenic risk score analysis in an independent biobank sample (BioVU, n=67,589) confirmed the genetic correlations between PAU and substance use and psychiatric disorders. Genetic heritability of PAU was enriched in brain and in conserved and regulatory genomic regions. Mendelian randomization suggested causal effects on liability to PAU of substance use, psychiatric status, risk-taking behavior, and cognitive performance. In summary, this large PAU meta-analysis identified novel risk loci and revealed genetic relationships with numerous other traits.

doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

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Objective: Anxiety disorders are common and often disabling. The goal of this study was to examine the genetic architecture of anxiety disorders and anxiety symptoms, which are also frequently comorbid with other mental disorders, such as major depressive disorder.Methods: Using one of the world's largest biobanks including genetic, environmental, and medical information, the Million Veteran Program, the authors performed a genome-wide association study (GWAS) of a continuous trait for anxiety (based on score on the Generalized Anxiety Disorder 2-item scale [GAD-2], N=199,611) as the primary analysis and selfreport of physician diagnosis of anxiety disorder (N=224,330) as a secondary analysis. Results:The authors identified five genome-wide significant signals for European Americans and one for African Americans on GAD-2 score. The strongest were on chromosome 3 (rs4603973) near SATB1, a global regulator of gene expression, and on chromosome 6 (rs6557168) near ESR1, which encodes an estrogen receptor. The locus identified on chromosome 7 (rs56226325, MAF=0.17) near MAD1L1 was previously identified in GWASs of bipolar disorder and schizophrenia. The authors replicated these findings in the summary statistics of two major published GWASs for anxiety, and also found evidence of significant genetic correlation between the GAD-2 score results and previous GWASs for anxiety (r g =0.75), depression (r g =0.81), and neuroticism (r g =0.75).Conclusions: This is the largest GWAS of anxiety traits to date. The authors identified novel genome-wide significant associations near genes involved with global regulation of gene expression (SATB1) and the estrogen receptor alpha (ESR1). Additionally, the authors identified a locus (MAD1L1) that may have implications for genetic vulnerability across several psychiatric disorders. This work provides new insights into genetic risk mechanisms underpinning anxiety and related psychiatric disorders.

Importance Posttraumatic stress disorder (PTSD) is a prevalent, serious public health concern, particularly in the military. The identification of genetic risk factors for PTSD may provide important insights into the biological basis of vulnerability and comorbidity. Objective To discover genetic loci associated with lifetime PTSD risk in two cohorts from the Army Study To Assess Risk and Resilience in Servicemembers (Army STARRS). Design, Setting and Participants Two coordinated genomewide association studies of mental health in the US military: New Soldier Study (NSS, N=3167 cases and 4607 trauma-exposed controls) and Pre/Post Deployment Study (PPDS, N=947 cases and 4969 trauma-exposed controls). The primary analysis compared lifetime DSM-IV PTSD cases to trauma-exposed controls without lifetime PTSD. Main Outcomes and Measures Association analyses were conducted for PTSD using logistic regression models within each of 3 ancestral groups (European, African, Latino) by study and then meta-analyzed. Heritability and genetic correlation and pleiotropy with other psychiatric and immune-related disorders were estimated. Results We observed a genomewide significant locus in ANKRD55 on chromosome 5 (rs159572; odds ratio [OR] = 1.62, p-value =2.43×10−8; adjusted for cumulative trauma exposure [AOR] = 1.68, p-value = 1.18×10−8) in the African American samples from NSS. We also observed a genomewide significant locus in or near ZNF626 on chromosome 19 (rs11085374; OR = 0.77, p-value = 4.59 ×10−8) in the European American samples from NSS. We did not find similar results for either SNP in the corresponding ancestry group from the PPDS sample, or in other ancestral groups or trans-ancestral meta-analyses. SNP-based heritability was non-significant, and no significant genetic correlations were observed between PTSD and six mental disorders and nine immune-related disorders. Significant evidence of pleiotropy was observed between PTSD and rheumatoid arthritis and, to a lesser extent, psoriasis. Conclusions and Relevance In the largest GWAS of PTSD to date, involving a US military sample, we found limited evidence of association for specific loci. Further efforts are needed to replicate the genomewide significant association with ANKRD55 – associated in prior research with several autoimmune and inflammatory disorders – and to clarify the nature of the genetic overlap observed between PTSD and rheumatoid arthritis and psoriasis.