Genome ‐wide meta‐analysis identifies a novel susceptibility signal at CACNA2D3 for nicotine dependence

Nicotine dependence (ND) has a reported heritability of 40–70%. Low‐coverage whole‐genome sequencing was conducted in 1,889 samples from the UCSF Family study. Linear mixed models were used to conduct genome‐wide association (GWA) tests of ND in this and five cohorts obtained from the database of Genotypes and Phenotypes. Fixed‐effect meta‐analysis was carried out separately for European (n = 14,713) and African (n = 3,369) participants, and then in a combined analysis of both ancestral groups. The meta‐analysis of African participants identified a significant and novel susceptibility signal (rs56247223; p = 4.11 × 10−8). Data from the Genotype‐Tissue Expression (GTEx) study suggested the protective allele is associated with reduced mRNA expression of CACNA2D3 in three human brain tissues (p < 4.94 × 10−2). Sequence data from the UCSF Family study suggested that a rare nonsynonymous variant in this gene conferred increased risk for ND (p = 0.01) providing further support for CACNA2D3 involvement in ND. Suggestive associations were observed in six additional regions in both European and merged populations (p < 5.00 × 10−6). The top variants were found to regulate mRNA expression levels of genes in human brains using GTEx data (p < 0.05): HAX1 and CHRNB2 (rs1760803), ADAMTSL1 (rs17198023), PEX2 (rs12680810), GLIS3 (rs12348139), non‐coding RNA for LINC00476 (rs10759883), and GABBR1 (rs56020557 and rs6239...
Source: American Journal of Medical Genetics Part B: Neuropsychiatric Genetics - Category: Genetics & Stem Cells Authors: Tags: RESEARCH ARTICLE Source Type: research