Positive Selection on Loci Associated with Drug and Alcohol Dependence.
paper
Primary
Public
- Authors
- Sadler, Brooke; Haller, Gabe; Edenberg, Howard; Tischfield, Jay; Brooks, Andy; Kramer, John; Schuckit, Marc; Nurnberger, John; Goate, Alison
- Year
- 2015
- Journal
- PloS one
- PMID
- 26270548
- DOI
- 10.1371/journal.pone.0134393
- PMCID
- PMC4536217
Much of the evolution of human behavior remains a mystery, including how certain disadvantageous behaviors are so prevalent. Nicotine addiction is one such phenotype. Several loci have been implicated in nicotine related phenotypes including the nicotinic receptor gene clusters (CHRNs) on chromosomes 8 and 15. Here we use 1000 Genomes sequence data from 3 populations (Africans, Asians and Europeans) to examine whether natural selection has occurred at these loci. We used Tajima's D and the integrated haplotype score (iHS) to test for evidence of natural selection. Our results provide evidence for strong selection in the nicotinic receptor gene cluster on chromosome 8, previously found to be significantly associated with both nicotine and cocaine dependence, as well as evidence selection acting on the region containing the CHRNA5 nicotinic receptor gene on chromosome 15, that is genome wide significant for risk for nicotine dependence. To examine the possibility that this selection is related to memory and learning, we utilized genetic data from the Collaborative Studies on the Genetics of Alcoholism (COGA) to test variants within these regions with three tests of memory and learning, the Wechsler Adult Intelligence Scale (WAIS) Block Design, WAIS Digit Symbol and WAIS Information tests. Of the 17 SNPs genotyped in COGA in this region, we find one significantly associated with WAIS digit symbol test results. This test captures aspects of reaction time and memory, suggesting that a phenotype relating to memory and learning may have been the driving force behind selection at these loci. This study could begin to explain why these seemingly deleterious SNPs are present at their current frequencies.
Tajima’s D and iHS Results.A-CTajima’s D andD-F) iHS for the LCT region on chromosome 2, the CHRNA3-B4-A5 gene cluster on chromosome 15 and the CHRNB3-A6 gene cluster on chromosome 8 across individuals of European (red), African (Purple) or Asian (green) ancestry. Lines are the 95% confidence intervals as calculated by permutation for iHS and Tajima’s D.
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External
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|---|---|---|---|---|
| Discovery of runs-of-homozygosity diplotype clusters and their associations with diseases in UK Biobank. | Naseri A et al. | — | 2024 | → |
| Combined genetic influence of the nicotinic receptor gene cluster CHRNA5/A3/B4 on nicotine dependence. | Lee SH et al. | — | 2018 | → |
| Genetic epidemiology of familial Mediterranean fever through integrative analysis of whole genome and exome sequences from Middle East and North Africa. | Koshy R et al. | — | 2018 | → |
| Pleiotropic effects of Chr15q25 nicotinic gene cluster and the relationship between smoking, cognition and ADHD. | Schuch JB et al. | — | 2016 | → |