Using genome-wide complex trait analysis to quantify 'missing heritability' in Parkinson's disease

Keller, M.F., Saad, M. and Bras, J. et al. (2012) Using genome-wide complex trait analysis to quantify 'missing heritability' in Parkinson's disease. Human Molecular Genetics, 21 (22), 4996-5009. (doi:10.1093/hmg/dds335). (PMID:22892372)

Abstract

Genome-wide association studies (GWASs) have been successful at identifying single-nucleotide polymorphisms (SNPs) highly associated with common traits; however, a great deal of the heritable variation associated with common traits remains unaccounted for within the genome. Genome-wide complex trait analysis (GCTA) is a statistical method that applies a linear mixed model to estimate phenotypic variance of complex traits explained by genome-wide SNPs, including those not associated with the trait in a GWAS. We applied GCTA to 8 cohorts containing 7096 case and 19 455 control individuals of European ancestry in order to examine the missing heritability present in Parkinson's disease (PD). We meta-analyzed our initial results to produce robust heritability estimates for PD types across cohorts. Our results identify 27% (95% CI 17–38, P = 8.08E ? 08) phenotypic variance associated with all types of PD, 15% (95% CI ?0.2 to 33, P = 0.09) phenotypic variance associated with early-onset PD and 31% (95% CI 17–44, P = 1.34E ? 05) phenotypic variance associated with late-onset PD. This is a substantial increase from the genetic variance identified by top GWAS hits alone (between 3 and 5%) and indicates there are substantially more risk loci to be identified. Our results suggest that although GWASs are a useful tool in identifying the most common variants associated with complex disease, a great deal of common variants of small effect remain to be discovered.

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Contributors

Author: Karen Morrison

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