Online citations, reference lists, and bibliographies.
← Back to Search

Finding The Missing Heritability Of Complex Diseases

T. Manolio, F. Collins, N. Cox, D. Goldstein, L. Hindorff, D. Hunter, M. McCarthy, E. Ramos, L. Cardon, A. Chakravarti, J. Cho, A. Guttmacher, A. Kong, L. Kruglyak, E. Mardis, C. Rotimi, M. Slatkin, D. Valle, A. Whittemore, M. Boehnke, A. Clark, E. Eichler, G. Gibson, J. Haines, T. Mackay, S. McCarroll, P. Visscher
Published 2009 · Biology, Medicine

Cite This
Download PDF
Analyze on Scholarcy
Share
Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, ‘missing’ heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.
This paper references
Detailed review of strengths, weaknesses and controversies in estimations of heritability from human
P M Visscher (2008)
10.1038/ng0208-129
A treasure trove for lipoprotein biology
A. Lusis (2008)
Genetic dissection of human blood pressure variation: common pathways from rare phenotypes.
R. Lifton (2004)
10.1086/507611
2005 William Allan Award address. No longer just looking under the lamppost.
F. Collins (2006)
10.1002/(SICI)1521-1878(200004)22:4<372::AID-BIES7>3.0.CO;2-J
Canalization in evolutionary genetics: a stabilizing theory?
Garth A. Gibson (2000)
The 1000 Genomes Project : analysis of pilot datasets
G. R. Abecasis (2008)
10.1038/ng.287
Six new loci associated with body mass index highlight a neuronal influence on body weight regulation
Cristen J. Willer (2009)
3 microdeletions increase risk of idiopathic generalized epilepsy
I Helbig (2009)
10.1093/hmg/ddn289
Genome-wide association studies: potential next steps on a genetic journey.
M. McCarthy (2008)
10.1038/ng.381
Genome-wide association study and meta-analysis finds over 40 loci affect risk of type 1 diabetes
J. Barrett (2009)
10.1038/ng.291
Common variants at 30 loci contribute to polygenic dyslipidemia
S. Kathiresan (2009)
10.1038/ng.207
Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus
K. Yasuda (2008)
The 1000 Genomes Project: analysis of pilot datasets. Biology of Genomes page 246
G. R. Abecasis (2009)
A catalog of published genome-wide association studies
L. A. Hindorff (2009)
10.1097/GIM.0b013e3181b13a6c
The Scientific Foundation for Personal Genomics: Recommendations from a National Institutes of Health–Centers for Disease Control and Prevention Multidisciplinary Workshop
M. Khoury (2009)
10.1038/ng.290
Variants in MTNR1B influence fasting glucose levels
I. Prokopenko (2009)
10.1017/CBO9781139167222
Anthropological Genetics: Methods
M. Crawford (2006)
10.1086/500026
Using linkage genome scans to improve power of association in genome scans.
K. Roeder (2006)
10.1038/nrg2346
Advances in autism genetics: on the threshold of a new neurobiology
B. Abrahams (2008)
Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes
J. Barrett (2010)
10.1371/journal.pgen.0020041
Assumption-Free Estimation of Heritability from Genome-Wide Identity-by-Descent Sharing between Full Siblings
P. Visscher (2006)
10.1038/35015718
Searching for genetic determinants in the new millennium
N. Risch (2000)
10.1038/ng.327
Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants
S. Kathiresan (2009)
10.1038/ng.216
Detection of sharing by descent, long-range phasing and haplotype imputation
A. Kong (2008)
10.1038/ng.93
A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures
A. Sharp (2008)
Joint linkage of multiple loci for a complex disorder.
C. Maclean (1993)
10.1371/journal.pgen.1000540
Prediction and Interaction in Complex Disease Genetics: Experience in Type 1 Diabetes
D. Clayton (2009)
10.1038/nature07229
Large recurrent microdeletions associated with schizophrenia
H. Stefánsson (2008)
10.1073/PNAS.0508483103
Multiple rare variants in NPC1L1 associated with reduced sterol absorption and plasma low-density lipoprotein levels.
J. Cohen (2006)
10.1126/science.1167728
Rare Variants of IFIH1, a Gene Implicated in Antiviral Responses, Protect Against Type 1 Diabetes
S. Nejentsev (2009)
10.1086/324069
Genomewide scans of complex human diseases: true linkage is hard to find.
J. Altmüller (2001)
10.1038/ng0508-489
Sizing up human height variation
P. Visscher (2008)
10.1126/SCIENCE.1138659
Strong Association of De Novo Copy Number Mutations with Autism
J. Sebat (2007)
10.1038/nature06862
Mapping and sequencing of structural variation from eight human genomes
J. Kidd (2008)
10.1038/nrg2322
Heritability in the genomics era — concepts and misconceptions
P. Visscher (2008)
10.1126/science.273.5281.1516
The Future of Genetic Studies of Complex Human Diseases
N. Risch (1996)
10.1038/ng.354
Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2
S. Ahmed (2009)
10.1016/j.ajhg.2008.06.024
Methods for detecting associations with rare variants for common diseases: application to analysis of sequence data.
Bingshan Li (2008)
10.1086/321272
Are rare variants responsible for susceptibility to complex diseases?
J. Pritchard (2001)
10.1056/NEJMra0808700
Genomewide association studies and human disease.
J. Hardy (2009)
10.1038/ng1873
Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration
J. Maller (2006)
10.1056/NEJMoa0805384
Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes.
H. Mefford (2008)
A catalog of published genome-wide association studies. Available at AEhttp://www
L A Hindorff (2009)
International Consortium for Systemic Lupus Erythematosus Genetics (SLEGEN)
10.1038/nature07239
Rare chromosomal deletions and duplications increase risk of schizophrenia
J. Stone (2008)
10.1126/SCIENCE.8346443
Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.
E. H. Corder (1993)
10.1371/journal.pgen.1000337
Interpretation of Genetic Association Studies: Markers with Replicated Highly Significant Odds Ratios May Be Poor Classifiers
J. Jakobsdottir (2009)
10.1146/annurev.genom.9.081307.164258
African genetic diversity: implications for human demographic history, modern human origins, and complex disease mapping.
M. Campbell (2008)
10.1001/jama.299.11.1335
How to interpret a genome-wide association study.
T. Pearson (2008)
10.1093/hmg/ddn282
Extending genome-wide association studies to copy-number variation.
S. McCarroll (2008)
10.1038/ng.81
Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci
J. Harley (2008)
A catalog of published genome-wide association studies
L. A. Hindorff (2009)
10.1056/NEJMc081550
Polygenes, risk prediction, and targeted prevention of breast cancer.
R. Wilkins (2008)
10.1017/S0140525X06009095
Resolving the paradox of common, harmful, heritable mental disorders: which evolutionary genetic models work best?
M. Keller (2006)
10.1097/00125817-200203000-00002
A comprehensive review of genetic association studies
J. Hirschhorn (2002)
Introduction to Quantitative Genetics Addison 123 (Wesley
D. S. Falconer (1996)
THE BIOLOGY OF GENOMES
S. Celniker (2010)
10.1016/S0168-9525(01)02410-6
On the allelic spectrum of human disease.
David E. Reich (2001)
10.1038/ng.175
Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease
J. Barrett (2008)
10.1038/ng.271
Genome-wide association analysis of metabolic traits in a birth cohort from a founder population
C. Sabatti (2009)
10.2307/2528001
Introduction to Quantitative Genetics.
A. W. Edwards (1961)
10.1038/ng.120
Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes
E. Zeggini (2008)
10.1073/pnas.0903103106
Potential etiologic and functional implications of genome-wide association loci for human diseases and traits
L. Hindorff (2009)
10.1111/j.1469-1809.2007.00406.x
Shared Genomic Segment Analysis. Mapping Disease Predisposition Genes in Extended Pedigrees Using SNP Genotype Assays
A. Thomas (2008)
10.1086/508571
Test for interaction between two unlinked loci.
J. Zhao (2006)
10.1038/ng.249
Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci
J. Cooper (2008)
Genome-wide association of earlyonset myocardial infarction with single nucleotide polymorphisms and copy number variants
(2009)
10.1038/ng.292
15q13.3 microdeletions increase risk of idiopathic generalized epilepsy
I. Helbig (2009)
10.1038/ng.313
Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis
R. Cid (2009)
10.1086/500615
A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol.
Ingrid K. Kotowski (2006)
10.1086/491719
Diagnostic genome profiling in mental retardation.
B. D. de Vries (2005)
10.5860/choice.45-3270
:Anthropological Genetics: Theory, Methods and Applications
A. Buchanan (2007)
10.1038/ng2015
Multiple regions within 8q24 independently affect risk for prostate cancer
C. Haiman (2007)
Comprehensive analysis of genomic annotations for disease-associated SNPs defined by GWAS, showing great majority of associated loci in intronic or intergenic regions of unknown function
10.1093/HMG/11.20.2417
The allelic architecture of human disease genes: common disease-common variant...or not?
J. Pritchard (2002)
10.1038/ng0706-731
Statistical false positive or true disease pathway?
J. Todd (2006)
10.1016/j.tig.2007.12.007
The impact of next-generation sequencing technology on genetics.
E. Mardis (2008)
10.1038/456018a
Personal genomes: The case of the missing heritability
B. Maher (2008)
10.1038/nrg2344
Genome-wide association studies for complex traits: consensus, uncertainty and challenges
M. McCarthy (2008)
REVIEWS NATUREjVol
(2009)
10.1038/ng2093
Challenges and standards in integrating surveys of structural variation
S. Scherer (2007)
Prediction of total genetic value using genome-wide dense marker maps.
T. Meuwissen (2001)
10.1038/nrg2502
Decanalization and the origin of complex disease
G. Gibson (2009)
10.1038/ng.238
Integrated detection and population-genetic analysis of SNPs and copy number variation
S. McCarroll (2008)
10.1371/journal.pgen.1000231
Predicting Unobserved Phenotypes for Complex Traits from Whole-Genome SNP Data
S. Lee (2008)
Macmillan Publishers Limited. All Rights Reserved ©2012
A. Kong
10.1038/nature06258
A second generation human haplotype map of over 3.1 million SNPs
K. Frazer (2007)
10.1126/SCIENCE.278.5343.1580
Variations on a Theme: Cataloging Human DNA Sequence Variation
F. Collins (1997)
10.1038/ng.162
Strong association of de novo copy number mutations with sporadic schizophrenia
B. Xu (2008)
10.1093/hmg/ddn307
Copy number variations and risk for schizophrenia in 22q11.2 deletion syndrome
A. Bassett (2008)
10.1038/ng.318
Genome-wide association study identifies a novel breast cancer susceptibility locus at 6q25.1
W. Zheng (2009)
10.1158/1055-9965.EPI-08-1142
Generalizability of Associations from Prostate Cancer Genome-Wide Association Studies in Multiple Populations
Kevin M Waters (2009)
10.1080/09571730185200281
REVIEWS
N. Norman (1934)
10.1038/ng.215
Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn's disease
S. McCarroll (2008)
10.1038/ng1984
Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL
S. Romeo (2007)
10.4103/0256-4947.65261
Autism spectrum disorders
H. Faras (2010)
10.1056/NEJMoa075974
Association between microdeletion and microduplication at 16p11.2 and autism.
L. A. Weiss (2008)
Introduction to Quantitative Genetics Addison
DS. Falconer (1996)
A catalog of published genome-wide association
LA. Hindorff (2009)
10.1038/ng.75
Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans
S. Kathiresan (2008)



This paper is referenced by
10.1176/appi.ajp.2010.10091340
After GWAS: searching for genetic risk for schizophrenia and bipolar disorder.
E. Gershon (2011)
10.1038/ng.817
Bias due to selection of rare variants using frequency in controls
C. Johansen (2011)
Quick, "Imputation-free" meta-analysis with
Markus Leber (2012)
10.11606/T.42.2012.TDE-09112012-105715
BUSCA DE FATORES GENÉTICOS ASSOCIADOS À RESPOSTA AO TRATAMENTO DO HCV GENÓTIPO 3
Alexandre La Luna (2012)
10.1101/cshperspect.a006296
The genetics of Alzheimer disease.
R. Tanzi (2012)
10.1215/9780822376729-008
Social Categories and Laboratory Practices in Brazil, Colombia, and Mexico: A Comparative Overview
Peter Wade (2014)
10.1201/B18027-11
Utilizing Markov chains to model ion channel sequence variation and kinetics
Fodor Anthony (2015)
10.1002/9781119095910.CH12
Critical Issues in Genetic Association Studies
Elizabeth Prom-Wormley (2017)
Asma en la infancia y factores asociados en el área sanitaria de Pontevedra
Tania Liñares Mata (2015)
10.25560/10142
Detection of novel obesity loci in Asian populations
Rajkumar Dorajoo (2012)
the 1000 Genomes Project has been instrumental in clarifying the ubiquity of rare variants and their importance to the study of human disease
Ian B. Gibson (2013)
Title: Genomics and transcriptomics in drug discovery
Joaquín Dopazo (2013)
10.1201/B14587-3
Longevity Assurance by Genome Maintenance
Paul Hasty (2013)
Cardiovascular Disease and Cardiovascular Risk Factors Subgroups at high risk for ischaemic heart disease: identification and validation in 67000 individuals from the general population
Ruth Frikke-Schmidt (2015)
The Pat ho genes is o f Obes it y fr o m a Geno mic and Sy s t ems Bio lo gy Per s p ect iv e
Candace Levian (2014)
10.1186/s13148-015-0062-8
The IGF1 P2 promoter is an epigenetic QTL for circulating IGF1 and human growth
M. Ouni (2015)
10.1111/jipb.12294
A haplotype block associated with thousand-kernel weight on chromosome 5DS in common wheat (Triticum aestivum L.).
Yuquan Wang (2015)
Identification and Characterization of Novel CYP2A6 Variants in African American Slow Nicotine Metabolizers
Mark Piliguian (2014)
Leveraging genetic association data to investigate the polygenic architecture of human traits and diseases
Ying Leong Chan (2014)
Genetics of environmental sensitivity and its moderating effects on mental health outcomes
Elham Assary (2019)
10.1007/978-981-13-8177-5
Genome-Wide Association Studies
Bjarke Feenstra (2008)
THE HISTORY OF NON-CODING DISCOVERIES
(2015)
10.1097/j.pain.0000000000000938
Neuropathic pain phenotyping by international consensus (NeuroPPIC) for genetic studies: a NeuPSIG systematic review, Delphi survey, and expert panel recommendations: Erratum.
Peter R. Kamermanb (2017)
10.4172/2155-6180.1000e126
Using Ancestral Information to Inform Analyses of Complex Data Sets
Katherine L. Thompson (2013)
SINGLE NUCLEOTIDE POLYMORPHISMS IN VITAMIN A, FOLATE AND CHOLINE RELATED GENES AND INTERACTION WITH MATERNAL VITAMIN INTAKE AND NEUROBLASTOMA
Angela L Mazul (2016)
Genome Wide Association Studies Discovering Genetic Susceptibility Alleles for Human Cancers
Zhaoming Wang (2013)
10.18632/oncotarget.19287
Identification of five genetic variants as novel determinants of type 2 diabetes mellitus in Japanese by exome-wide association studies.
Y. Yamada (2017)
The genetic epidemiology and omics of age-related cataract
Ekaterina Yonova-Doing (2018)
Genetic studies of complex autoimmune disease
Alexandra Gyllenberg (2014)
Pathway Selection for GWAS Using the Group Lasso with Overlaps
Matt Silver ()
2 The Human Genome Project : Where AreWe Now and Where Are We Going ?
S. Kumar (2018)
Genetic risk score based on statistical learning
Florian Privé (2019)
See more
Semantic Scholar Logo Some data provided by SemanticScholar