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PMID: 25307299 Published · ppublish English Journal Article Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't

Structural architecture of SNP effects on complex traits.

American journal of human genetics ·Vol. 95 ·No. 5 ·2014-11-06 ·Pages 477-89

Gamazon ER, Cox NJ, Davis LK

Abstract

Despite the discovery of copy-number variation (CNV) across the genome nearly 10 years ago, current SNP-based analysis methodologies continue to collapse the homozygous (i.e., A/A), hemizygous (i.e., A/0), and duplicative (i.e., A/A/A) genotype states, treating the genotype variable as irreducible or unaltered by other colocalizing forms of genetic (e.g., structural) variation. Our understanding of common, genome-wide CNVs suggests that the canonical genotype construct might belie the enormous complexity of the genome. Here we present multiple analyses of several phenotypes and provide methods supporting a conceptual shift that embraces the structural dimension of genotype. We comprehensively investigate the impact of the structural dimension of genotype on (1) GWAS methods, (2) interpretation of rare LOF variants, (3) characterization of genomic architecture, and (4) implications for mapping loci involved in complex disease. Taken together, these results argue for the inclusion of a structural dimension and suggest that some portion of the "missing" heritability might be recovered through integration of the structural dimension of SNP effects on complex traits.

MeSH Terms
DNA Copy Number Variations/genetics Genetic Variation Genome-Wide Association Study/methods Models, Genetic Phenotype Polymorphism, Single Nucleotide/genetics
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Gamazon Eric R
Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
Cox Nancy J
Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
Davis Lea K
Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA. Electronic address: [email protected].
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Article Info
Journal
American journal of human genetics
Abbr.
Am J Hum Genet
ISSN
1537-6605
DOI
10.1016/j.ajhg.2014.09.009
Email
[email protected]
Published
2014-11-06
Epub
2014-00-09
Pages
477-89
Language
English
Region
United States
NLM ID
0370475
PMCID
PMC4225594
Subset
IM
Grants
NIGMS NIH HHS · U01 GM061393 · United States
NCATS NIH HHS · KL2TR000431 · United States
NIDDK NIH HHS · P60 DK20595 · United States
Wellcome Trust · 076113 · United Kingdom
NIMH NIH HHS · P50MH94267 · United States
NIGMS NIH HHS · U19 GM61393 · United States
NICHD NIH HHS · P50 HD055751 · United States
Intramural NIH HHS · United States
NIMH NIH HHS · R01 MH101820 · United States
NIMH NIH HHS · R01 MH090937 · United States
NIDDK NIH HHS · P30 DK020595 · United States
NIDDK NIH HHS · P60 DK020595 · United States
NCATS NIH HHS · UL1 TR000430 · United States
NHGRI NIH HHS · U01 HG005773 · United States
NCATS NIH HHS · KL2 TR000431 · United States
NIMH NIH HHS · P50 MH094267 · United States
External Links
PubMed source DOI: 10.1016/j.ajhg.2014.09.009 PMC Full Text View journal details
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