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Am J Hum Genet DOI:10.1016/j.ajhg.2014.02.006

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

Publication TypeJournal Article
Year of Publication2014
AuthorsChan, Y, Lim, ET, Sandholm, N, Wang, SR, McKnight, AJayne, Ripke, S, Daly, MJ, Neale, BM, Salem, RM, Hirschhorn, JN
Corporate AuthorsDIAGRAM consortium, GENIE Consortium, GIANT Consortium, IIBDGC Consortium, PGC Consortium
JournalAm J Hum Genet
Date Published2014 Mar 06
KeywordsAlbuminuria, Colitis, Ulcerative, Crohn Disease, Diabetes Mellitus, Type 2, Diabetic Nephropathies, Genetic Variation, Genome-Wide Association Study, Humans, Kidney Failure, Chronic, Mental Disorders, Models, Statistical, Multifactorial Inheritance, Obesity, Odds Ratio, Phenotype, Risk

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.


Alternate JournalAm. J. Hum. Genet.
PubMed ID24607388
PubMed Central IDPMC3951950
Grant ListR01 DK075787 / DK / NIDDK NIH HHS / United States
R01 DK081923 / DK / NIDDK NIH HHS / United States
R01DK075787 / DK / NIDDK NIH HHS / United States
R01DK081923 / DK / NIDDK NIH HHS / United States