Disease and polygenic architecture: avoid trio design and appropriately account for unscreened control subjects for common disease

Peyrot, Wouter J., Boomsma, Dorret I., Penninx, Brenda W. J. H. and Wray, Naomi R. (2016) Disease and polygenic architecture: avoid trio design and appropriately account for unscreened control subjects for common disease. American Journal of Human Genetics, 98 2: 382-391. doi:10.1016/j.ajhg.2015.12.017


Author Peyrot, Wouter J.
Boomsma, Dorret I.
Penninx, Brenda W. J. H.
Wray, Naomi R.
Title Disease and polygenic architecture: avoid trio design and appropriately account for unscreened control subjects for common disease
Journal name American Journal of Human Genetics   Check publisher's open access policy
ISSN 1537-6605
0002-9297
Publication date 2016-02-04
Year available 2016
Sub-type Article (original research)
DOI 10.1016/j.ajhg.2015.12.017
Open Access Status Not Open Access
Volume 98
Issue 2
Start page 382
End page 391
Total pages 10
Place of publication Cambridge, MA, United States
Publisher Cell Press
Collection year 2017
Language eng
Formatted abstract
Genome-wide association studies (GWASs) are an optimal design for discovery of disease risk loci for diseases whose underlying genetic architecture includes many common causal loci of small effect (a polygenic architecture). We consider two designs that deserve careful consideration if the true underlying genetic architecture of the trait is polygenic: parent-offspring trios and unscreened control subjects. We assess these designs in terms of quantification of the total contribution of genome-wide genetic markers to disease risk (SNP heritability) and power to detect an associated risk allele. First, we show that trio designs should be avoided when: (1) the disease has a lifetime risk > 1%; (2) trio probands are ascertained from families with more than one affected sibling under which scenario the SNP heritability can drop by more than 50% and power can drop as much as from 0.9 to 0.15 for a sample of 20,000 subjects; or (3) assortative mating occurs (spouse correlation of the underlying liability to the disorder), which decreases the SNP heritability but not the power to detect a single locus in the trio design. Some studies use unscreened rather than screened control subjects because these can be easier to collect; we show that the estimated SNP heritability should then be scaled by dividing by (1 - K × u)2 for disorders with population prevalence K and proportion of unscreened control subjects u. When omitting to scale appropriately, the SNP heritability of, for example, major depressive disorder (K = 0.15) would be underestimated by 28% when none of the control subjects are screened
Keyword Polygenic architecture
Unscreened control subjects
Trio design
Genome-wide association studies
GWAS
Disease risk
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Queensland Brain Institute Publications
 
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