Positive Selection on Loci Associated with Drug and Alcohol Dependence.
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.
Department of Psychiatry, Washington University, St. Louis, MO, United States of America.
Brooke
B
Sadler
Department of Orthopedic Surgery, Washington University, St. Louis, MO, United States of America.
Gabe
G
Haller
Department of Molecular Biology, Indiana University, Indianapolis, IN, United States of America.
Howard
H
Edenberg
Department of Genetics, Rutgers University, Piscataway, NJ, United States of America.
Jay
J
Tischfield
Department of Genetics, Rutgers University, Piscataway, NJ, United States of America.
Andy
A
Brooks
Department of Psychiatry, University of Iowa, Iowa City, IA, United States of America.
John
J
Kramer
Department of Psychiatry, University of San Diego, La Jolla, CA, United States of America.
Marc
M
Schuckit
Department of Psychiatry, Indiana University, Indianapolis, IN, United States of America.
John
J
Nurnberger
Department of Neuroscience, Mount Sinai, New York City, NY, United States of America.
Alison
A
Goate
D000328:Adult; D000437:Alcoholism / Q000235:genetics*; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D019970:Cocaine-Related Disorders / Q000235:genetics*; D030561:Databases, Nucleic Acid; D005260:Female; D056426:Genetic Loci; D006801:Humans; D008297:Male; D005810:Multigene Family; D009419:Nerve Tissue Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011978:Receptors, Nicotinic / Q000235:genetics
C447158:CHRNA5 protein, human; D009419:Nerve Tissue Proteins; D011978:Receptors, Nicotinic