Research & Projects

Methamphetamine use disorder dependence (MUD) is a hugely destructive public health problem that is surging worldwide, including in many parts of the US and Asia. Thailand is an optimal site for studying the genetics of methamphetamine dependence (MD), with less genetic and environmental heterogeneity than in the US, in the context of a devastating and widespread Thai epidemic. Dr Gelernter has formed international relationships and established logistical infrastructures necessary for human genetic studies of drug dependence, including MUD, in Thailand. Leveraging now-established and effective collaborations in Bangkok (Thanyarak Institute and Chulalongkorn University), we have now collected data on >5000 case and control subjects in Bangkok and Chiang Mai and obtained genomewide data on all of these. The work is ongoing and a renewal of the project is pending with NIDA.

This is the fourth iteration of the Psychiatric Genomics Consortium, including the Substance Use Disorders (SUD) group, which is co-led by Drs. Gelernter, Agarwal, and Edenberg. The goal is to conduct large meta- and mega-analyses of GWAS data with the aim of discovering new risk alleles and mechanisms for the many psychiatric traits of interest.

The Psychiatric Genomics Consortium is perhaps the most innovative and productive experiment in the history of psychiatry. The PGC unified the field and attracted a cadre of outstanding scientists (802 investigators from 157 institutions in 41 countries). Aim 1: we will continue to advance genetic discovery for severe psychiatric disorders in all working groups, systematically interface with large biobank studies to ensure maximal comparability, and aggressively promote new studies of individuals with psychiatric disorders from diverse ancestries to increase discovery and improve fine-mapping. Aim 2: most studies analyze common variation (Aim 1), rare CNV (Aim 2), and rare exome/genome resequencing results (via collaboration) in isolation: we will apply an integrative framework to rigorously evaluate the contributions of all measured types of genetic variation on risk for psychiatric disorders. Aim 3: we will move beyond classical case-control definitions to a more biologically-based and nuanced understanding by enabling large trans-diagnostic studies, convene trans-disciplinary teams to use genetics to address unresolved questions about the nature of psychiatric disorders, and to promote large studies of the severest cases seen in psychiatric practice (leveraging the global reach of PGC investigators). Aim 4: we will work to maximize the impact of our work via translational efforts: close collaborations with neuroscience consortia to understand the biological implications of our findings; work to identify modifiable causal risk factors; and work to robustly predict clinical outcomes and identify patient subsets. Aim 5: we will increase impact of our work by extending and formalizing outreach to different communities (including pharma and biotech), via digital media (Twitter, Facebook, Wikipedia), and by developing, distributing, and updating resources/educational material for patients, families, and medical professionals. These goals are consistent with a core mission of the NIMH, and the central idea of the PGC: to convert the family history risk factor into biologically, clinically, and therapeutically meaningful insights.

Dr. John Krystal is PI of this center, which supports projects and core resources devoted to translating basic neuroscience advances into clinical insights related to alcoholism. The Translational Technologies Core, co-led by Dr Gelernter, supports and provide expertise related to genetics and neuroimaging throughout the Center. Genetic factors are important in modulating risk of alcohol use disorder (AUD) and related traits. Genomewide association studies (GWAS) have identified multiple genetic risk loci for AUD, for problematic alcohol use, and for quantity-frequency measures such as AUDIT-C and drinks per week. Major function of the Genetics component will be to support microarray genotyping for each of the projects (including pilot projects) involving human subjects, for the purpose of identifying genotype/phenotype associations based on polygenic risk scores (PRS) of AUD and related traits. Most GWAS have focused on European-ancestry populations; we will also use the best available methodology to study non-European populations in a PRS context. Genetics component investigators advise Center investigators on issues related to genetics studies. We also bring to bear a rich dataset of GWASed subjects with alcohol and other substance dependencies that can be used to test hypothesis related to Center findings and goals; and we will continue pilot work in related topics of interest, e.g., epigenetics and transcriptomics of alcohol dependence. We do a great deal of alcohol-related research with the MVP sample as well, and these projects – MVP and CTNA – interact frequently.

Major Goals: Alcohol dependence (AD) in the United States is highly destructive and costly to individuals and society. We previously conducted an AD research project focused on the understudied African-American (AA) population. Compared to most studies of European-ancestry subjects, studies to date of AAs have often been underpowered due to both inadequate sample size and insufficient genomewide coverage. Additional recruitment of AA AD subjects with a state-of-the-art assessment is necessary, and that is the goal of the present project. Deep phenotyping will make available other relevant related phenotypes.

The aims of this study are to identify risk loci for PTSD and related traits in the context of the Million Veteran Program and to conduct extensive post-GWAS analyses. Posttraumatic stress disorder (PTSD) is a major problem among military Veterans, yet its pathophysiology is poorly understood. The Veterans Affairs (VA) Million Veteran Program (MVP) is an ideal setting for study of this problem, and we are carried out a Cooperative Studies Program project (CSP#575B), in the MVP context, to identify genetic risk factors relevant to PTSD and related traits. This work includes a set of extended analyses in a larger sample, and post-GWAS analyses. With more subjects there is increased power to map relevant traits; we will continue GWAS of PTSD and related traits in the expanded sample, using a set of related diagnosis definitions in an effort to dissect the genetic components of the PTSD trait. There is very high comorbidity of PTSD with substance use disorder traits; we have explored SUDs as well, including alcohol, cannabis, opioid, nicotine, cannabis, and cocaine use disorders, as well as caffeine use. We have investigated polygenic overlap between PTSD and numerous related traits. We also study traits phenotypically associated with PTSD, such as cognitive decline, Alzheimer’s disease, persistent post-concussive symptoms, and immune-related disorders (such as Crohn’s disease, rheumatoid arthritis, and multiple sclerosis) in the MVP sample. We use approaches that permit testing of causality among these correlated traits (e.g., Mendelian Randomization, MR). Finally, the MVP sample is suitable for advancing work in many populations that are generally understudied. We will investigate psychiatric trait-relevant population genetics of African-Americans, Latinos, East Asians, and South Asians, and other populations in the MVP system, and we work to maximize information from, and identify results relevant to, all populations. Ongoing projects in this sample include studies of physical activity and sugar intake and its effect on psychiatric traits.

The goal is to study the genetic bases of psychiatric disorders in patients receiving treatment at VA hospital systems nationwide. A biobank of at least 50,000 participants will be created for future sequencing, epigenetic, transcriptomic, and proteomic studies. The study is just getting underway as of early 2023 – as data collection continues it will provide many opportunities for research and training.

With this project, we aim to continue our work in the genetics of methamphetamine dependence in Thailand, establishing a substance use disorder and mental health-focused biobank. The participants will undergo 3x whole genome sequencing and we plan to complete genomewide association analysis followed by a series of in-silico studies.

With this project, we hope to complete extensive GWAS and meta-analyses for trauma- and stress-related disorders, especially post-traumatic stress disorder and major depression, followed by detailed post-GWAS analyses intended to improve our understanding of the underlying biology of these disorders.