Family-based genome-wide association study of frontal θ oscillations identifies potassium channel gene KCNJ6.
- Authors
- Kang, S J; Rangaswamy, M; Manz, N; Wang, J-C; Wetherill, L; Hinrichs, T; Almasy, L; Brooks, A; Chorlian, D B; Dick, D; Hesselbrock, V; Kramer, J; Kuperman, S; Nurnberger, J; Rice, J; Schuckit, M; Tischfield, J; Bierut, L J; Edenberg, H J; Goate, A; Foroud, T; Porjesz, B
- Year
- 2012
- Journal
- Genes, brain, and behavior
- PMID
- 22554406
- DOI
- 10.1111/j.1601-183X.2012.00803.x
- PMCID
- PMC3666338
Event-related oscillations (EROs) represent highly heritable neuroelectric correlates of cognitive processes that manifest deficits in alcoholics and in offspring at high risk to develop alcoholism. Theta ERO to targets in the visual oddball task has been shown to be an endophenotype for alcoholism. A family-based genome-wide association study was performed for the frontal theta ERO phenotype using 634 583 autosomal single nucleotide polymorphisms (SNPs) genotyped in 1560 family members from 117 families densely affected by alcohol use disorders, recruited in the Collaborative Study on the Genetics of Alcoholism. Genome-wide significant association was found with several SNPs on chromosome 21 in KCNJ6 (a potassium inward rectifier channel; KIR3.2/GIRK2), with the most significant SNP at P = 4.7 × 10(-10)). The same SNPs were also associated with EROs from central and parietal electrodes, but with less significance, suggesting that the association is frontally focused. One imputed synonymous SNP in exon four, highly correlated with our top three SNPs, was significantly associated with the frontal theta ERO phenotype. These results suggest KCNJ6 or its product GIRK2 account for some of the variations in frontal theta band oscillations. GIRK2 receptor activation contributes to slow inhibitory postsynaptic potentials that modulate neuronal excitability, and therefore influence neuronal networks.
Manhattan plot of genome-wide association results for theta ERO at FzNegative log-transformed p- values for SNPs are plotted against position on each chromosome. One genomic region on chromosome 21 contains SNPs that exceed the genome-wide significance threshold of 7.88 × 10−8 (indicated by red line).
Plot of chromosome 21q22 association with theta power at Fz. Negative log-transformed p- values for SNPs are plotted against position on chromosome 21q22* indicates genotyped SNP# indicates synonymous coding SNP
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