An Assessment of the Individual and Collective Effects of Variants on Height Using Twins and a Developmentally Informative Study Design

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In a sample of 3,187 twins and 3,294 of their parents, we sought to investigate association of both individual variants and a genotype-based height score involving 176 of the 180 common genetic variants with adult height identified recently by the GIANT consortium. First, longitudinal observations on height spanning pre-adolescence through adulthood in the twin sample allowed us to investigate the separate effects of the previously identified SNPs on pre-pubertal height and pubertal growth spurt. We show that the effect of SNPs identified by the GIANT consortium is primarily on prepubertal height. Only one SNP, rs7759938 in LIN28B, approached a significant association with pubertal growth. Second, we show how using the twin data to control statistically for environmental variance can provide insight into the ultimate magnitude of SNP effects and consequently the genetic architecture of a phenotype. Specifically, we computed a genetic score by weighting SNPs according to their effects as assessed via meta-analysis. This weighted score accounted for 9.2% of the phenotypic variance in height, but 14.3% of the corresponding genetic variance. Longitudinal samples will be needed to understand the developmental context of common genetic variants identified through GWAS, while genetically informative designs will be helpful in accurately characterizing the extent to which these variants account for genetic, and not just phenotypic, variance.

Vyšlo v časopise: An Assessment of the Individual and Collective Effects of Variants on Height Using Twins and a Developmentally Informative Study Design. PLoS Genet 7(12): e32767. doi:10.1371/journal.pgen.1002413
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002413

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1. MacgregorSCornesBKMartinNGVisscherPM 2006 Bias, precision and heritability of self-reported and clinically measured height in Australian twins. Hum Genet 120 571 580

2. SilventoinenKSammalistoSPerolaMBoomsmaDICornesBK 2003 Heritability of adult body height: A comparative study of twin cohorts in eight countries. Twin Res 6 399 408

3. VisscherPMHillWGWrayNR 2008 Heritability in the genomics era - concepts and misconceptions. Nat Rev Genet 9 255 266

4. MaherB 2008 Personal genomes: The case of the missing heritability. Nature 456 18 21

5. ManolioTACollinsFSCoxNJGoldsteinDBHindorffLA 2009 Finding the missing heritability of complex diseases. Nature 461 747 753

6. YangJABenyaminBMcEvoyBPGordonSHendersAK 2010 Common SNPs explain a large proportion of the heritability for human height. Nature Genetics 42 565-U131

7. AllenHLEstradaKLettreGBerndtSIWeedonMN 2010 Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467 832 838

8. OkashaMGunnellDHollyJSmithGD 2002 Childhood growth and adult cancer. Best Pract Res Cl En 16 225 241

9. TannerJMWhitehouseRHTakaishiM 1966 Standards from Birth to Maturity for Height, Weight, Height Velocity, and Weight Velocity: British Children, 1965. Part II. Archives of Disease in Childhood 41 613 635

10. SilventoinenKPietilainenKHTyneliusPSorensenTIAKaprioJ 2008 Genetic regulation of growth from birth to 18 years of age: The Swedish young male twins study. Am J Hum Biol 20 292 298

11. IaconoWGMcGueM 2002 Minnesota Twin Family Study. Twin Res 5 482 487

12. PalmertMRBoepplePA 2001 Variation in the timing of puberty: Clinical spectrum and genetic investigation. J Clin Endocr Metab 86 2364 2368

13. SalemRMO'ConnorDTSchorkNJ 2010 Curve-based multivariate distance matrix regression analysis: application to genetic association analyses involving repeated measures. Physiol Genomics 42 236 247

14. PinheiroJCBatesDM 2000 Mixed-effects models in S and S-PLUS New York Springer xvi 528

15. NealeMCCardonLR 1992 Methodology for genetic studies of twins and families Dortrecht, The Netherlands Kluwer Academic

16. VisscherPMYangJAGoddardME 2010 A Commentary on ‘Common SNPs Explain a Large Proportion of the Heritability for Human Height’ by Yang et al. (2010). Twin Research and Human Genetics 13 517 524

17. PetersenACCrockettLRichardsMBoxerA 1988 A self-report measure of pubertal status: reliability, validity, and initial norms. Journal of Youth and Adolescence 17 117 133

18. R Development Core Team 2011 R: A language and environment for statistical computing Vienna R Foundation for Statistical Computing

19. BokerSNealeMMaesHWildeMSpiegelM 2011 OpenMx: An Open Source Extended Structural Equation Modeling Framework. Psychometrika 76 306 317 doi:10.1007/S11336-010-9200-6

20. MillerMBBasuSCunninghamJOettingWSchorkNJ submitted The Minnesota Center for Twin and Family Research Genome-Wide Association Study.

21. LiYWillerCJDingJScheetPAbecasisGR 2010 MaCH: Using Sequence and Genotype Data to Estimate Haplotypes and Unobserved Genotypes. Genet Epidemiol 34 816 834

22. LiYWillerCSannaSAbecasisG 2009 Genotype Imputation. Annu Rev Genom Hum G 10 387 406

23. PriceALPattersonNJPlengeRMWeinblattMEShadickNA 2006 Principal components analysis corrects for stratification in genome-wide association studies. Nature Genetics 38 904 909

24. LiXBasuSMillerMBIaconoWGMcGueM 2011 A Rapid Generalized Least Squares Model for a Genome-Wide Quantitative Trait Association Analysis in Families. Hum Hered 71 67 82

25. ZhuHShahSShyh-ChangNShinodaGEinhornWS 2010 Lin28a transgenic mice manifest size and puberty phenotypes identified in human genetic association studies. Nature Genetics 42 626-U106

26. WidenERipattiSCousminerDLSurakkaILappalainenT 2010 Distinct Variants at LIN28B Influence Growth in Height from Birth to Adulthood. Am J Hum Genet 86 773 782

27. HindorffLASethupathyPJunkinsHARamosEMMehtaJP 2009 Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. P Natl Acad Sci USA 106 9362 9367

28. SovioUMook-KanamoriDOWarringtonNMLawrenceRBriollaisL 2011 Association between Common Variation at the FTO Locus and Changes in Body Mass Index from Infancy to Late Childhood: The Complex Nature of Genetic Association through Growth and Development. PLoS Genet 7 e1001307 doi:10.1371/journal.pgen.1001307

29. UitterlindenAGPerryJRBStolkLFranceschiniNLunettaKL 2009 Meta-analysis of genome-wide association data identifies two loci influencing age at menarche. Nature Genetics 41 648 650

30. OngKKElksCELiSXZhaoJHLuanJ 2009 Genetic variation in LIN28B is associated with the timing of puberty. Nature Genetics 41 729 733

31. BurtSAMcGueMDemarteJAKruegerRFIaconoWG 2006 Timing of menarche and the origins of conduct disorder. Arch Gen Psychiat 63 890 896