Missing heritability and GWAS utility.
作者： Clifton Bogardus
DOI: 10.1038/OBY.2008.613
关键词: Genome-wide association study 、 Missing heritability problem 、 Additive genetic effects 、 Population 、 FTO gene 、 Twin study 、 Heritability 、 Genetics 、 Candidate gene 、 Biology
摘要: The environment is largely responsible for differences in BMI between populations; genetics within populations. Evidences support of the environmental effect are many. prevalence obesity differs greatly countries, even among developed countries (1). On a smaller scale, “built environment” city associated with BMI. In New York City greater density bus and subway stops variety uses land neighborhood lower BMIs (2). Closely genetically related populations living different environments differ considerably average (3). clearly can be more or less obesegenic. But there strong evidence that population variance determined. weight adoptees correlates better their biologic parents than adoptive (4). Twin studies indicate about two-thirds attributable to additive genetic factors (5). most convincing study heritability twins was Stunkard colleagues, who studied 93 adult pairs monozygotic had been separated as young children reared apart (6). These authors similarly estimated due factors. What these factors? Two experimental approaches have used identify susceptibility genes humans: candidate gene approach an agnostic method using single-nucleotide polymorphisms (SNPs) genome-wide association (GWAS). Candidate selected screened variants based on physiology molecular mechanisms energy homeostasis animals. Very few obese humans causative thought major constituents this homeostatic system (7). one exception melanocortin 4 receptor (MC4R). About two half percent severely individuals (8). increased food intake but also reduced expenditure (9). GWASs commonly common disease, including obesity. done European descent ~350,000 SNPs, covering 75% genome (10,11). findings were noncoding SNPs intron FTO SNP presumed regularly site 188 kb downstream MC4R gene. ~77,000 adults difference 1.17kg/m2 compound homozygotes risk alleles (1% population) vs. nonrisk (19% population). account 2% combined results GWAS very little heritable.
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