PuSH - Publication Server of Helmholtz Zentrum München

Chan, Y.* ; Lim, E.T.* ; Sandholm, N.* ; Wang, S.R.* ; McKnight, A.J.* ; Ripke, S.* ; DIAGRAM Consortium (Gieger, C. ; Grallert, H. ; Illig, T. ; Klopp, N. ; Müller-Nurasyid, M. ; Peters, A.) ; GENIE Consortium (*) ; IIBDGC Consortium (*) ; GIANT Consortium (Albrecht, E. ; Heid, I.M. ; Thorand, B. ; Wichmann, H.-E.) ; Daly, M.J.* ; Neale, B.M.* ; Salem, R.M.* ; Hirschhorn, J.N.*

An excess of risk-increasing low-frequency variants can be a signal of polygenic inheritance in complex diseases.

Am. J. Hum. Genet. 94, 437-452 (2014)
DOI
Open Access Green as soon as Postprint is submitted to ZB.
In most complex diseases, much of the heritability remains unaccounted for by common variants. It has been postulated that lower-frequency variants contribute to the remaining heritability. Here, we describe a method to test for polygenic inheritance from lower-frequency variants by using GWAS summary association statistics. We explored scenarios with many causal low-frequency variants and showed that there is more power to detect risk variants than to detect protective variants, resulting in an increase in the ratio of detected risk to protective variants (R/P ratio). Such an excess can also occur if risk variants are present and kept at lower frequencies because of negative selection. The R/P ratio can be falsely elevated because of reasons unrelated to polygenic inheritance, such as uneven sample sizes or asymmetric population stratification, so precautions to correct for these confounders are essential. We tested our method on published GWAS results and observed a strong signal in some diseases (schizophrenia and type 2 diabetes) but not others. We also explored the shared genetic component in overlapping phenotypes related to inflammatory bowel disease (Crohn disease [CD] and ulcerative colitis [UC]) and diabetic nephropathy (macroalbuminuria and end-stage renal disease [ESRD]). Although the signal was still present when both CD and UC were jointly analyzed, the signal was lost when macroalbuminuria and ESRD were jointly analyzed, suggesting that these phenotypes should best be studied separately. Thus, our method may also help guide the design of future genetic studies of various traits and diseases.
Altmetric
Additional Metrics?
[➜Log in]
Edit extra informations Login
Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Genome-wide Association; Inflammatory-bowel-disease; Genetic Architecture; Missing Heritability; Ulcerative-colitis; Provides Insights; Common Snps; Metaanalysis; Loci; Susceptibility
ISSN (print) / ISBN 0002-9297
e-ISSN 1537-6605
Journal American Journal of Human Genetics, The
Quellenangaben Volume: 94, Issue: 3, Pages: 437-452 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place New York, NY
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) CCG Nutrigenomics and Type 2 Diabetes (KKG-KDN)
Institute of Epidemiology II (EPI2)
Institute of Genetic Epidemiology (IGE)