Year: 2020
Type: article
Abstract: There is evidence across several species for genetic control of phenotypic variation of complex traits1–4, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using 170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype)5–7, is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of 0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI8, possibly mediated by DNA methylation9,10. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.
DOI: 10.17615/yvv7-bx40
Authors: Hua Zhao, Jing, Demirkan, Ayşe, Hadley, David, Palmer, Cameron, Medland, Sarah E., Loos, Ruth J. F., Kapur, Karen, Luan, Jian’an, Speliotes, Elizabeth K., Monda, Keri L., Fischer, Krista, Huffman, Jennifer E., Esko, Tõnu, Thorleifsson, Gudmar, Isaacs, Aaron, Yerges-Armstrong, Laura M., Li, Guo, Chasman, Daniel I., White, Charles, Yang, Jian, Jackson, Anne U., Powell, Joseph E., Mahajan, Anubha, Vernon Smith, Albert, Mägi, Reedik, Steinthorsdottir, Valgerdur, Vitart, Veronique, Feitosa, Mary F., Waite, Lindsay, Heard-Costa, Nancy L., Rose, Lynda M., Wang, Sophie R.
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Awards: Validation and Replication of Genes Associated with Common Human Disease Using Australian Twin Families, Molecular Epidemiology of Alcoholism 3 - EDAC Families, Uncoupled Research Fellowship, G3199409182, G3862454230, Genome-wide combined linkage-association scan of multiply phenotyped twin sibships, Pigmentation genes and melanoma risk, Association Screen of Migraine Candidate Genes, Why have large genome scans of common variation not explained more of the familial risk for diseases?, Why is most of the genetic variance for complex traits undetected by large powerful screens of common variants?, Mapping Genes for typical migraine using twin families., Accurate prediction of individual risk to disease using multiple genetic risk factors, Genetics of moliness, Uncoupled Research Fellowship, Genetics of moliness, Better Methods for Individual Risk Prediction of Complex Traits in Human Populations, Molecular Epidemiology of Alcoholism 2- Big Sibships, PERSISTENCE AND CHANGE IN DRINKING HABITS--TWIN STUDY, Statistical Methods and Algorithms for Analysis of High-throughput Genetics and Genomics Platforms, G9000243987
OpenAlex ID: W2336830241