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Principal Investigator: Frank Wolfgang Albert
Organization: UNIVERSITY OF MINNESOTA
Fiscal Year: 2024
Award: $631,895
Funding agency: National Institute on Drug Abuse
Project Summary/Abstract
Drug and alcohol use and addiction are heritable phenotypes that are leading causes of
morbidity and mortality worldwide. Hundreds of loci have now been strongly linked to
risk for substance use and addiction, and many more genes remain to be discovered.
Studies of impactful rare genetic variants are accelerating our understanding of genetic
influences of complex disease and producing compelling targets for intervention
research and drug development. The current proposal provides a framework by which
rare variants can be efficiently identified and evaluated in humans for their effects on
addiction using large and readily available datasets. Such datasets often have sparse
phenotyping, especially for behavioral and psychiatric phenotypes. Our proposed
framework overcomes this challenge through re-contact and reassessment of rare
variant carriers and their family members, allowing measurement of psychiatric
phenotypes far beyond that available in biobanks. We take full advantage of a
multidisciplinary team, advanced genomic technology, diverse analytical approaches,
and detailed deep phenotypic assessment on a sample of large extended families. We
will use large highly-powered GWAS and whole genome sequencing datasets to identify
rare putatively deleterious variants within substance-use-associated loci. Upon
functional validation of the rare deleterious variant in cell lines, we will use a novel
procedure to impute such variants into the Michigan Genomics Initiative Biobank,
thereby identifying carriers of rare deleterious alleles. These individuals, and their
families, will be re-contacted and receive standard and tailored assessments of their
substance use/dependence history, psychiatric, neurocognitive, and psychosocial
function. The proposed framework offers a new approach to investigate the human
biology underlying GWAS hits, identifying therapeutic targets and improving our
understanding of the etiology of addiction.
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