Hang Zhou, PhD

The central goal of my graduate and postdoctoral work is to understand the human genome and how it affects human traits and diseases. To reach this goal, I completed training in population genetics during PhD and psychiatric genetics as postdoc. I performed a series of genetic studies on natural selection in the human genome and genome-wide studies on substance use disorders (SUDs) and comorbid psychiatric diseases. We were the first to study the shared genetic mechanism for SUDs and major depression comorbidity using genome-wide methods, identified a risk variant (SEMA3A) which specifically contributed to comorbid alcohol use disorder (AUD) and depression (Zhou et al., JAMA Psychiatry, 2017; highlighted by an Editorial paper in JAMA Psychiatry), and a risk variant in GRIA4 gene associated with comorbid nicotine dependence and depression (Zhou et al., Translational Psychiatry, 2018).

I was promoted to Associate Research Scientist in July 2018. During this period, I lead the analytic effort for several projects in the Million Veteran Program (MVP). We conducted the largest multi-ancestry genome-wide association study (GWAS) on alcohol consumption and AUD (Kranzler*, Zhou*, Kember* et al., Nature Communications, 2019), all five major US ancestry groups were included (African Americans, European Americans, Latino Americans, East Asian and South Asian Americans). This study delivered a key message that changed this field: AUD differs from alcohol consumption genetically. We accomplished, to our knowledge, the largest meta-analysis for problematic alcohol use (PAU) in European samples (N=435,563), tripled the number of risk variants associated with PAU (Zhou et al., Nature Neuroscience, 2020). In particular, we found that PAU is genetically correlated with many traits; phenome-wide polygenic risk score (PRS) analysis in an independent biobank (Vanderbilt University Biobank) confirmed the genetic correlations between PAU and substance use and psychiatric disorders; Mendelian randomization (MR) suggested that the liability to PAU was attributable in part to substance use, psychiatric status, risk-taking behavior and cognitive performance; and the genetic heritability of PAU was enriched in certain brain regions. We also conducted the largest-to-date genetic study of opioid use disorder (OUD) and identified functional coding variant Asn40Asp in OPRM1 associated with OUD (Zhou et al., JAMA Psychiatry, 2020). These studies made a noteworthy contribution to this field.

Currently, I am working on multiple projects in MVP, include comorbid AUD and mental disorders, and others. MVP has released the genotype data release 4 containing over 650,000 unique samples, which is presently the world’s largest genomic cohort connected to electronic health record data. I am also working on the whole exome sequencing (WES) data in Yale-Penn cohort (over 4,400 samples) for PAU and comorbid diseases (Brain Behavior Research Foundation 2018 NARSAD Young Investigator Award).

Future research plans

Based on my previous work, my future research will focus on three topics related to alcohol: 1) the genetic causality of alcohol intake and PAU on cancer risk; 2) genetics of sex differences in alcohol use and PAU; 3) advanced genetic study of PAU by incorporating WES, whole genome sequencing (WGS), functional magnetic resonance imaging (fMRI) data, and machine learning methodologies.