Home LiteratureArticle Details
PMID: 24141362 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Evaluating empirical bounds on complex disease genetic architecture.

Nature genetics ·Vol. 45 ·No. 12 ·2013-12-00 ·Pages 1418-27

Agarwala V, Flannick J, Sunyaev S, GoT2D Consortium, Altshuler D

Abstract

The genetic architecture of human diseases governs the success of genetic mapping and the future of personalized medicine. Although numerous studies have queried the genetic basis of common disease, contradictory hypotheses have been advocated about features of genetic architecture (for example, the contribution of rare versus common variants). We developed an integrated simulation framework, calibrated to empirical data, to enable the systematic evaluation of such hypotheses. For type 2 diabetes (T2D), two simple parameters--(i) the target size for causal mutation and (ii) the coupling between selection and phenotypic effect--define a broad space of architectures. Whereas extreme models are excluded by the combination of epidemiology, linkage and genome-wide association studies, many models remain consistent, including those where rare variants explain either little (<25%) or most (>80%) of T2D heritability. Ongoing sequencing and genotyping studies will further constrain the space of possible architectures, but very large samples (for example, >250,000 unselected individuals) will be required to localize most of the heritability underlying T2D and other traits characterized by these models.

MeSH Terms
Computer Simulation Diabetes Mellitus, Type 2/genetics Disease/genetics Empirical Research Genetic Linkage Genetic Predisposition to Disease Genetic Variation Genome-Wide Association Study Humans Models, Genetic Multifactorial Inheritance
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Agarwala Vineeta
1] Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [3] Program in Biophysics, Graduate School of Arts and Sciences, Harvard University, Cambridge, Massachusetts, USA. [4].
Flannick Jason
Sunyaev Shamil
GoT2D Consortium
Altshuler David
References (70)
70 references, click to expand
  1. Heritability of adult body height: a comparative study of twin cohorts in eight countries.
    Twin Res. 2003 Oct;6(5):399-408 PMID: 14624724
  2. Genetic mapping in human disease.
    Science. 2008 Nov 7;322(5903):881-8 PMID: 18988837
  3. Rare and common regulatory variation in population-scale sequenced human genomes.
    PLoS Genet. 2011 Jul;7(7):e1002144 PMID: 21811411
  4. Distribution of allele frequencies and effect sizes and their interrelationships for common genetic susceptibility variants.
    Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18026-31 PMID: 22003128
  5. The metabochip, a custom genotyping array for genetic studies of metabolic, cardiovascular, and anthropometric traits.
    PLoS Genet. 2012;8(8):e1002793 PMID: 22876189
  6. Genome-wide association studies for complex traits: consensus, uncertainty and challenges.
    Nat Rev Genet. 2008 May;9(5):356-69 PMID: 18398418
  7. Rare variants create synthetic genome-wide associations.
    PLoS Biol. 2010 Jan 26;8(1):e1000294 PMID: 20126254
  8. Common SNPs explain a large proportion of the heritability for human height.
    Nat Genet. 2010 Jul;42(7):565-9 PMID: 20562875
  9. Genetic heterogeneity in human disease.
    Cell. 2010 Apr 16;141(2):210-7 PMID: 20403315
  10. Estimating missing heritability for disease from genome-wide association studies.
    Am J Hum Genet. 2011 Mar 11;88(3):294-305 PMID: 21376301
  11. Risk of diabetes in siblings of index cases with Type 2 diabetes: implications for genetic studies.
    Diabet Med. 2002 Jan;19(1):41-50 PMID: 11869302
  12. Missing heritability and strategies for finding the underlying causes of complex disease.
    Nat Rev Genet. 2010 Jun;11(6):446-50 PMID: 20479774
  13. An abundance of rare functional variants in 202 drug target genes sequenced in 14,002 people.
    Science. 2012 Jul 6;337(6090):100-4 PMID: 22604722
  14. Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes.
    Nat Genet. 2012 Jan 29;44(3):297-301 PMID: 22286214
  15. Pooled association tests for rare variants in exon-resequencing studies.
    Am J Hum Genet. 2010 Jun 11;86(6):832-8 PMID: 20471002
  16. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes.
    Nat Genet. 2012 Sep;44(9):981-90 PMID: 22885922
  17. Linkage strategies for genetically complex traits. II. The power of affected relative pairs.
    Am J Hum Genet. 1990 Feb;46(2):229-41 PMID: 2301393
  18. Bayesian inference analyses of the polygenic architecture of rheumatoid arthritis.
    Nat Genet. 2012 Mar 25;44(5):483-9 PMID: 22446960
  19. A map of human genome variation from population-scale sequencing.
    Nature. 2010 Oct 28;467(7319):1061-73 PMID: 20981092
  20. Evidence of abundant purifying selection in humans for recently acquired regulatory functions.
    Science. 2012 Sep 28;337(6102):1675-8 PMID: 22956687
  21. Genetic risk prediction in complex disease.
    Hum Mol Genet. 2011 Oct 15;20(R2):R182-8 PMID: 21873261
  22. A rare penetrant mutation in CFH confers high risk of age-related macular degeneration.
    Nat Genet. 2011 Oct 23;43(12):1232-6 PMID: 22019782
  23. Resequencing of 200 human exomes identifies an excess of low-frequency non-synonymous coding variants.
    Nat Genet. 2010 Nov;42(11):969-72 PMID: 20890277
  24. Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes.
    Nat Genet. 2008 May;40(5):638-45 PMID: 18372903
  25. Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease.
    Nat Genet. 2011 Oct 09;43(11):1066-73 PMID: 21983784
  26. The importance of synthetic associations will only be resolved empirically.
    PLoS Biol. 2011 Jan 18;9(1):e1001008 PMID: 21267066
  27. Construction of multilocus genetic linkage maps in humans.
    Proc Natl Acad Sci U S A. 1987 Apr;84(8):2363-7 PMID: 3470801
  28. Identifying plausible genetic models based on association and linkage results: application to type 2 diabetes.
    Genet Epidemiol. 2012 Dec;36(8):820-8 PMID: 22865662
  29. Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL.
    Nat Genet. 2007 Apr;39(4):513-6 PMID: 17322881
  30. Prevalence of diabetes and high risk for diabetes using A1C criteria in the U.S. population in 1988-2006.
    Diabetes Care. 2010 Mar;33(3):562-8 PMID: 20067953
  31. A genome-wide comparison of the functional properties of rare and common genetic variants in humans.
    Am J Hum Genet. 2011 Apr 8;88(4):458-68 PMID: 21457907
  32. What is complex about complex disorders?
    Genome Biol. 2012 Jan 23;13(1):237 PMID: 22269335
  33. The mystery of missing heritability: Genetic interactions create phantom heritability.
    Proc Natl Acad Sci U S A. 2012 Jan 24;109(4):1193-8 PMID: 22223662
  34. On the allelic spectrum of human disease.
    Trends Genet. 2001 Sep;17(9):502-10 PMID: 11525833
  35. Medical sequencing at the extremes of human body mass.
    Am J Hum Genet. 2007 Apr;80(4):779-91 PMID: 17357083
  36. Genetic cardiovascular risk prediction: will we get there?
    Circulation. 2010 Nov 30;122(22):2323-34 PMID: 21147729
  37. Interpretation of association signals and identification of causal variants from genome-wide association studies.
    Am J Hum Genet. 2010 May 14;86(5):730-42 PMID: 20434130
  38. The allelic architecture of human disease genes: common disease-common variant...or not?
    Hum Mol Genet. 2002 Oct 1;11(20):2417-23 PMID: 12351577
  39. A twin-pronged attack on complex traits.
    Nat Genet. 1997 Dec;17(4):387-92 PMID: 9398838
  40. Epistatic selection between coding and regulatory variation in human evolution and disease.
    Am J Hum Genet. 2011 Sep 9;89(3):459-63 PMID: 21907014
  41. Clan genomics and the complex architecture of human disease.
    Cell. 2011 Sep 30;147(1):32-43 PMID: 21962505
  42. A high-resolution map of human evolutionary constraint using 29 mammals.
    Nature. 2011 Oct 12;478(7370):476-82 PMID: 21993624
  43. Meta-analysis of 23 type 2 diabetes linkage studies from the International Type 2 Diabetes Linkage Analysis Consortium.
    Hum Hered. 2008;66(1):35-49 PMID: 18223311
  44. Recent explosive human population growth has resulted in an excess of rare genetic variants.
    Science. 2012 May 11;336(6082):740-3 PMID: 22582263
  45. GCTA: a tool for genome-wide complex trait analysis.
    Am J Hum Genet. 2011 Jan 7;88(1):76-82 PMID: 21167468
  46. Demographic history and rare allele sharing among human populations.
    Proc Natl Acad Sci U S A. 2011 Jul 19;108(29):11983-8 PMID: 21730125
  47. ForSim: a tool for exploring the genetic architecture of complex traits with controlled truth.
    Bioinformatics. 2008 Aug 15;24(16):1821-2 PMID: 18565989
  48. Power of deep, all-exon resequencing for discovery of human trait genes.
    Proc Natl Acad Sci U S A. 2009 Mar 10;106(10):3871-6 PMID: 19202052
  49. Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease.
    Nat Genet. 2003 Mar;33 Suppl:228-37 PMID: 12610532
  50. The Genesis of Twins.
    Genetics. 1919 Sep;4(5):489-99 PMID: 17245935
  51. Implications of the Human Genome Project for medical science.
    JAMA. 2001 Feb 7;285(5):540-4 PMID: 11176855
  52. Deep resequencing reveals excess rare recent variants consistent with explosive population growth.
    Nat Commun. 2010 Nov 30;1:131 PMID: 21119644
  53. Genome-wide association studies for common diseases and complex traits.
    Nat Rev Genet. 2005 Feb;6(2):95-108 PMID: 15716906
  54. Calibrating a coalescent simulation of human genome sequence variation.
    Genome Res. 2005 Nov;15(11):1576-83 PMID: 16251467
  55. Genetic architecture of type 2 diabetes: recent progress and clinical implications.
    Diabetes Care. 2009 Jun;32(6):1107-14 PMID: 19460916
  56. Population genetics--making sense out of sequence.
    Nat Genet. 1999 Jan;21(1 Suppl):56-60 PMID: 9915503
  57. Detecting rare variant associations by identity-by-descent mapping in case-control studies.
    Genetics. 2012 Apr;190(4):1521-31 PMID: 22267498
  58. Properties and modeling of GWAS when complex disease risk is due to non-complementing, deleterious mutations in genes of large effect.
    PLoS Genet. 2013;9(2):e1003258 PMID: 23437004
  59. An evolutionary framework for association testing in resequencing studies.
    PLoS Genet. 2010 Nov 11;6(11):e1001202 PMID: 21085648
  60. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder.
    Nature. 2009 Aug 6;460(7256):748-52 PMID: 19571811
  61. Multiple rare variants in different genes account for multifactorial inherited susceptibility to colorectal adenomas.
    Proc Natl Acad Sci U S A. 2004 Nov 9;101(45):15992-7 PMID: 15520370
  62. Predictors of and longitudinal changes in insulin sensitivity and secretion preceding onset of type 2 diabetes.
    Diabetes. 2005 Jan;54(1):166-74 PMID: 15616025
  63. Personal genomes: The case of the missing heritability.
    Nature. 2008 Nov 6;456(7218):18-21 PMID: 18987709
  64. Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs.
    Nat Genet. 2012 Feb 19;44(3):247-50 PMID: 22344220
  65. Evolution in health and medicine Sackler colloquium: Genetic architecture of a complex trait and its implications for fitness and genome-wide association studies.
    Proc Natl Acad Sci U S A. 2010 Jan 26;107 Suppl 1:1752-6 PMID: 20133822
  66. Finding the missing heritability of complex diseases.
    Nature. 2009 Oct 8;461(7265):747-53 PMID: 19812666
  67. Uncovering the roles of rare variants in common disease through whole-genome sequencing.
    Nat Rev Genet. 2010 Jun;11(6):415-25 PMID: 20479773
  68. Using extended genealogy to estimate components of heritability for 23 quantitative and dichotomous traits.
    PLoS Genet. 2013 May;9(5):e1003520 PMID: 23737753
  69. Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia.
    Nat Genet. 2010 Aug;42(8):684-7 PMID: 20657596
  70. Heritability and familiality of type 2 diabetes and related quantitative traits in the Botnia Study.
    Diabetologia. 2011 Nov;54(11):2811-9 PMID: 21826484
Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.2804
Published
2013-12-00
Epub
2013-00-20
Pages
1418-27
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC4158716
Subset
IM
Grants
NIGMS NIH HHS · R01 GM078598 · United States
NIMH NIH HHS · R01MH084676 · United States
NIGMS NIH HHS · T32 GM007753 · United States
NIGMS NIH HHS · T32GM007748-33 · United States
NIGMS NIH HHS · T32 GM008313 · United States
NIGMS NIH HHS · R01GM078598 · United States
NIGMS NIH HHS · T32 GM007748 · United States
NIDDK NIH HHS · 1RC2DK088389-01 · United States
NIDDK NIH HHS · RC2 DK088389 · United States
NIGMS NIH HHS · T32GM008313 · United States
NIGMS NIH HHS · T32GM007753 · United States
NIMH NIH HHS · R01 MH084676 · United States
External Links
PubMed source DOI: 10.1038/ng.2804 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2