Milaneschi, Y. | bioRxiv Science

bioRxiv2018

Trans-ancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders

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 schizophrenia, ADHD, depression, and use of cigarettes and cannabis. There was only modest genetic correlation with alcohol consumption and inconsistent associations with problem drinking. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and non - pathological drinking behaviors.

genetics↗

bioRxiv2017

Genetic Architecture of Subcortical Brain Structures in Over 40,000 Individuals Worldwide

Subcortical brain structures are integral to motion, consciousness, emotions, and learning. We identified common genetic variation related to the volumes of nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen, and thalamus, using genome-wide association analyses in over 40,000 individuals from CHARGE, ENIGMA and the UK-Biobank. We show that variability in subcortical volumes is heritable, and identify 25 significantly associated loci (20 novel). Annotation of these loci utilizing gene expression, methylation, and neuropathological data identified 62 candidate genes implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

genetics↗