rs680244

This population-based study examined natural selection on nicotinic receptor gene clusters (CHRNB3-A6 on chromosome 8 and CHRNA5-A3-B4 on chromosome 15) using 1000 Genomes data from three populations. Using Tajima's D and integrated haplotype score (iHS) tests, the authors found strong evidence for positive selection in the CHRNB3-A6 region and moderate evidence in CHRNA5-A3-B4. These regions harbor variants previously associated with nicotine dependence (rs16969968, rs1451240) and cocaine dependence. To understand the target of selection, the authors tested variants in COGA subjects (N=492) for association with cognitive phenotypes (WAIS tests) and found one significant association: rs7017612 with WAIS Digit Symbol score (β=0.43, p=0.003), suggesting memory and learning may be the driving force behind selection.

This association study screened 93 SNPs in 19 cholinergic genes (CHAT, CHRM1-5, CHRNA1-7, CHRNA9-10, CHRNB1-4) in two bipolar disorder (BD) pedigree series: NIMH Genetics Initiative (474 samples, 152 families) and Clinical Neurogenetics (83 samples, 22 families). Sib-TDT analysis showed nominally significant association for four SNPs (CHRNA2 rs7017417 P=0.024, CHRNA5 rs514743 P=0.031, CHRNB1 rs2302762 P=0.049, CHRNB4 rs1948 P=0.031), but none reached gene-wide significance after multiple testing correction. The authors conclude that these 19 cholinergic genes are unlikely to play a major role in BD predisposition in these pedigrees.