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Reproducible Risk Loci and Psychiatric Comorbidities in Anxiety: Results from ~200,000 Million Veteran Program Participants

By Daniel F Levey, Joel Gelernter, Renato Polimanti, Hang Zhou, Zhongshan Cheng, Mihaela Aslan, Rachel Quaden, John Concato, Krishnan Radhakrishnan, Julien Bryois, Patrick F Sullivan, the Million Veteran Program, Murray B Stein

Posted 05 Feb 2019
bioRxiv DOI: 10.1101/540245

We used GWAS in the Million Veteran Program sample (nearly 200,000 informative individuals) using a continuous trait for anxiety (GAD-2) to identify 5 genome-wide significant (GWS) signals for European Americans (EA) and 1 for African Americans. The strongest findings were on chromosome 3 (rs4603973, p=7.40×10-11) near the SATB1 locus, a global regulator of gene expression and on chromosome 6 (rs6557168, p=1.04×10-9) near ESR1 which encodes estrogen receptor &alpha. A locus identified on chromosome 7 near MAD1L1 (p=1.62×10-8) has been previously identified in GWAS of bipolar disorder and of schizophrenia and may represent a risk factor for psychiatric disorders broadly. SNP-based heritability was estimated to be ~6% for GAD-2. We also GWASed for self-reported anxiety disorder diagnoses (N=224,330) and identified two GWS loci, one (rs35546597, MAF=0.42, p=1.88×10-8) near the AURKB locus, and the other (rs10534613, MAF=0.41, p=4.92×10-8) near the IQCHE and MAD1L1 locus identified in the GAD-2 analysis. We demonstrate reproducibility by replicating our top findings in the summary statistics from the Anxiety NeuroGenetics Study (ANGST) and a UK Biobank neuroticism GWAS. We also replicated top findings from a large UK Biobank preprint, demonstrating stability of GWAS findings in complex traits once sufficient power is attained. Finally, we found evidence of significant genetic overlap between anxiety and major depression using polygenic risk scores, but also found that the main anxiety signals are independent of those for MDD. This work presents novel insights into the neurobiological risk underpinning anxiety and related psychiatric disorders.

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