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. 2014 Jun;19(6):717-23.
doi: 10.1038/mp.2013.99. Epub 2013 Aug 20.

Genome-wide association study of cocaine dependence and related traits: FAM53B identified as a risk gene

J Gelernter  1 , R Sherva  2 , R Koesterer  2 , L Almasy  3 , H Zhao  4 , H R Kranzler  5 , L Farrer  6
Affiliations

Genome-wide association study of cocaine dependence and related traits: FAM53B identified as a risk gene

J Gelernter et al. Mol Psychiatry. 2014 Jun.

Abstract

We report a genome-wide association study (GWAS) for cocaine dependence (CD) in three sets of African- and European-American subjects (AAs and EAs, respectively) to identify pathways, genes and alleles important in CD risk. The discovery GWAS data set (n=5697 subjects) was genotyped using the Illumina OmniQuad microarray (8 90 000 analyzed single-nucleotide polymorphisms (SNPs)). Additional genotypes were imputed based on the 1000 Genomes reference panel. Top-ranked findings were evaluated by incorporating information from publicly available GWAS data from 4063 subjects. Then, the most significant GWAS SNPs were genotyped in 2549 independent subjects. We observed one genome-wide-significant (GWS) result: rs2629540 at the FAM53B ('family with sequence similarity 53, member B') locus. This was supported in both AAs and EAs; P-value (meta-analysis of all samples)=4.28 × 10(-8). The gene maps to the same chromosomal region as the maximum peak we observed in a previous linkage study. NCOR2 (nuclear receptor corepressor 2) SNP rs150954431 was associated with P=1.19 × 10(-9) in the EA discovery sample. SNP rs2456778, which maps to CDK1 ('cyclin-dependent kinase 1'), was associated with cocaine-induced paranoia in AAs in the discovery sample only (P=4.68 × 10(-8)). This is the first study to identify risk variants for CD using GWAS. Our results implicate novel risk loci and provide insights into potential therapeutic and prevention strategies.

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Conflict of interest statement

Conflict of Interest

Although unrelated to the current study, Dr. Kranzler has been a consultant or advisory board member for Alkermes, Lilly, Lundbeck, Pfizer, and Roche. He is also a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which is supported by Lilly, Lundbeck, Abbott, and Pfizer.

Figures

Figure 1
Figure 1
Regional Manhattan plot for FAM53B, showing the meta-analysis P-value from EAs and AAs in the discovery and SAGE, as well as a single point for the phase 1–3 meta-analysis result (the highest purple dot on the graph). Since the result is driven primarily by AAs, the LD heat map is based on AAs also. Imputed SNPs are shown as circles, and genotyped SNPs as squares.
Figure 2
Figure 2
Manhattan plot, CD case/control analysis, EA population (discovery sample)
Figure 3
Figure 3
Q/Q plot for same. Other Q/Q plots similarly showed negligible inflation.
See this image and copyright information in PMC

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