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Am J Hum Genet. 2014 Nov 6;95(5):477-89. doi: 10.1016/j.ajhg.2014.09.009. Epub 2014 Oct 9.

Structural architecture of SNP effects on complex traits.

Author information

1
Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
2
Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA. Electronic address: lea.k.davis@gmail.com.

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.

PMID:
25307299
PMCID:
PMC4225594
DOI:
10.1016/j.ajhg.2014.09.009
[Indexed for MEDLINE]
Free PMC Article

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