Common Variants Show Predicted Polygenic Effects on Height in the Tails of the Distribution, Except in Extremely Short Individuals
Common genetic variants have been shown to explain a fraction of the inherited variation for many common diseases and quantitative traits, including height, a classic polygenic trait. The extent to which common variation determines the phenotype of highly heritable traits such as height is uncertain, as is the extent to which common variation is relevant to individuals with more extreme phenotypes. To address these questions, we studied 1,214 individuals from the top and bottom extremes of the height distribution (tallest and shortest ∼1.5%), drawn from ∼78,000 individuals from the HUNT and FINRISK cohorts. We found that common variants still influence height at the extremes of the distribution: common variants (49/141) were nominally associated with height in the expected direction more often than is expected by chance (p<5×10−28), and the odds ratios in the extreme samples were consistent with the effects estimated previously in population-based data. To examine more closely whether the common variants have the expected effects, we calculated a weighted allele score (WAS), which is a weighted prediction of height for each individual based on the previously estimated effect sizes of the common variants in the overall population. The average WAS is consistent with expectation in the tall individuals, but was not as extreme as expected in the shortest individuals (p<0.006), indicating that some of the short stature is explained by factors other than common genetic variation. The discrepancy was more pronounced (p<10−6) in the most extreme individuals (height<0.25 percentile). The results at the extreme short tails are consistent with a large number of models incorporating either rare genetic non-additive or rare non-genetic factors that decrease height. We conclude that common genetic variants are associated with height at the extremes as well as across the population, but that additional factors become more prominent at the shorter extreme.
Vyšlo v časopise:
Common Variants Show Predicted Polygenic Effects on Height in the Tails of the Distribution, Except in Extremely Short Individuals. PLoS Genet 7(12): e32767. doi:10.1371/journal.pgen.1002439
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002439
Souhrn
Common genetic variants have been shown to explain a fraction of the inherited variation for many common diseases and quantitative traits, including height, a classic polygenic trait. The extent to which common variation determines the phenotype of highly heritable traits such as height is uncertain, as is the extent to which common variation is relevant to individuals with more extreme phenotypes. To address these questions, we studied 1,214 individuals from the top and bottom extremes of the height distribution (tallest and shortest ∼1.5%), drawn from ∼78,000 individuals from the HUNT and FINRISK cohorts. We found that common variants still influence height at the extremes of the distribution: common variants (49/141) were nominally associated with height in the expected direction more often than is expected by chance (p<5×10−28), and the odds ratios in the extreme samples were consistent with the effects estimated previously in population-based data. To examine more closely whether the common variants have the expected effects, we calculated a weighted allele score (WAS), which is a weighted prediction of height for each individual based on the previously estimated effect sizes of the common variants in the overall population. The average WAS is consistent with expectation in the tall individuals, but was not as extreme as expected in the shortest individuals (p<0.006), indicating that some of the short stature is explained by factors other than common genetic variation. The discrepancy was more pronounced (p<10−6) in the most extreme individuals (height<0.25 percentile). The results at the extreme short tails are consistent with a large number of models incorporating either rare genetic non-additive or rare non-genetic factors that decrease height. We conclude that common genetic variants are associated with height at the extremes as well as across the population, but that additional factors become more prominent at the shorter extreme.
Zdroje
1. VisscherPMMacgregorSBenyaminBZhuGGordonS 2007 Genome partitioning of genetic variation for height from 11,214 sibling pairs. Am J Hum Genet 81 1104 1110
2. Lango AllenHEstradaKLettreGBerndtSIWeedonMN 2010 Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature
3. EichlerEEFlintJGibsonGKongALealSM 2010 Missing heritability and strategies for finding the underlying causes of complex disease. Nat Rev Genet 11 446 450
4. CirulliETGoldsteinDB 2010 Uncovering the roles of rare variants in common disease through whole-genome sequencing. Nat Rev Genet 11 415 425
5. ManolioTACollinsFSCoxNJGoldsteinDBHindorffLA 2009 Finding the missing heritability of complex diseases. Nature 461 747 753
6. ShamPCChernySSPurcellSHewittJK 2000 Power of linkage versus association analysis of quantitative traits, by use of variance-components models, for sibship data. Am J Hum Genet 66 1616 1630
7. LanderESBotsteinD 1989 Mapping mendelian factors underlying quantitative traits using RFLP linkage maps. Genetics 121 185 199
8. RischNZhangH 1995 Extreme discordant sib pairs for mapping quantitative trait loci in humans. Science 268 1584 1589
9. Van GestelSHouwing-DuistermaatJJAdolfssonRvan DuijnCMVan BroeckhovenC 2000 Power of selective genotyping in genetic association analyses of quantitative traits. Behav Genet 30 141 146
10. AbecasisGRCooksonWOCardonLR 2001 The power to detect linkage disequilibrium with quantitative traits in selected samples. Am J Hum Genet 68 1463 1474
11. DuncanELDanoyPKempJPLeoPJMcCloskeyE Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk. PLoS Genet 7 e1001372 doi:10.1371/journal.pgen.1001372
12. CotsapasCSpeliotesEKHatoumIJGreenawaltDMDobrinR 2009 Common body mass index-associated variants confer risk of extreme obesity. Hum Mol Genet 18 3502 3507
13. HegeleRABanMRHsuehNKennedyBACaoH 2009 A polygenic basis for four classical Fredrickson hyperlipoproteinemia phenotypes that are characterized by hypertriglyceridemia. Hum Mol Genet 18 4189 4194
14. GueyLTKravicJMelanderOBurttNPLaramieJM 2011 Power in the phenotypic extremes: a simulation study of power in discovery and replication of rare variants. Genet Epidemiol
15. AllisonDBHeoMSchorkNJWongSLElstonRC 1998 Extreme selection strategies in gene mapping studies of oligogenic quantitative traits do not always increase power. Hum Hered 48 97 107
16. HolmenJMidthjellKKrügerØLanghammerAHolmenT 2003 The Nord-Trøndelag Health Study 1995–97 (HUNT 2): Objectives, contents, methods and participation.. Science And Technology 13 19 32
17. VartiainenELaatikainenTPeltonenMJuoleviAMannistoS 2009 Thirty-five-year trends in cardiovascular risk factors in Finland. Int J Epidemiol 39 504 518
18. PurcellSNealeBTodd-BrownKThomasLFerreiraMA 2007 PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81 559 575
19. PriceALPattersonNJPlengeRMWeinblattMEShadickNA 2006 Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38 904 909
20. JohnsonADHandsakerREPulitSLNizzariMMO'DonnellCJ 2008 SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics 24 2938 2939
21. EgyudMRGajdosZKButlerJLTischfieldSLe MarchandL 2009 Use of weighted reference panels based on empirical estimates of ancestry for capturing untyped variation. Hum Genet 125 295 303
22. PritchardJKStephensMDonnellyP 2000 Inference of population structure using multilocus genotype data. Genetics 155 945 959
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2011 Číslo 12
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
Najčítanejšie v tomto čísle
- Targeted Proteolysis of Plectin Isoform 1a Accounts for Hemidesmosome Dysfunction in Mice Mimicking the Dominant Skin Blistering Disease EBS-Ogna
- The RNA Silencing Enzyme RNA Polymerase V Is Required for Plant Immunity
- The FGFR4-G388R Polymorphism Promotes Mitochondrial STAT3 Serine Phosphorylation to Facilitate Pituitary Growth Hormone Cell Tumorigenesis
- Hierarchical Generalized Linear Models for Multiple Groups of Rare and Common Variants: Jointly Estimating Group and Individual-Variant Effects