Linkage analysis followed by association show NRG1 associated with cannabis dependence in African Americans.
- Authors
- Han, Shizhong; Yang, Bao-Zhu; Kranzler, Henry R; Oslin, David; Anton, Raymond; Farrer, Lindsay A; Gelernter, Joel
- Year
- 2012
- Journal
- Biological psychiatry
- PMID
- 22520967
- DOI
- 10.1016/j.biopsych.2012.02.038
- PMCID
- PMC3699339
BACKGROUND: A genetic contribution to cannabis dependence (CaD) has been established but susceptibility genes for CaD remain largely unknown. METHODS: We employed a multistage design to identify genetic variants underlying CaD. We first performed a genome-wide linkage scan for CaD in 384 African American (AA) and 354 European American families ascertained for genetic studies of cocaine and opioid dependence. We then conducted association analysis under the linkage peak, first using data from a genome-wide association study from the Study of Addiction: Genetics and Environment, followed by replication studies of prioritized single nucleotide polymorphisms (SNPs) in independent samples. RESULTS: We identified the strongest linkage evidence with CaD (logarithm of odds = 2.9) on chromosome 8p21.1 in AAs. In the association analysis of the Study of Addiction: Genetics and Environment sample under the linkage peak, we identified one SNP (rs17664708) associated with CaD in both AAs (odds ratio [OR] = 2.93, p = .0022) and European Americans (OR = 1.38, p = .02). This SNP, located at NRG1, a susceptibility gene for schizophrenia, was prioritized for further study. We replicated the association of rs17664708 with CaD in an independent AAs sample (OR = 2.81, p = .0068). The joint analysis of the two AA samples demonstrated highly significant association between rs17664708 and CaD with adjustment for either global (p = .00044) or local ancestry (p = .00075). CONCLUSIONS: Our study shows that NRG1 is probably a susceptibility gene for CaD, based on convergent evidence of linkage and replicated associations in two independent AA samples.
Genomewide non-parametric linkage results in AAs and EAs. The black and red virtue lines represent the empirical genomewide suggestive (significant) linkage thresholds for AAs and EAs, respectively.
LLM interpretation
This is a Manhattan-style linkage plot showing LOD scores across 22 chromosomes for African-Americans (black line) and European-Americans (red line). The x-axis represents the chromosomes and the y-axis represents the LOD score. Neither group reaches the "Genomewide significant linkage" threshold (top dashed line), though the African-American group shows a peak on chromosome 8 that exceeds the "Genomewide suggestive linkage" threshold (bottom dashed line).
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