An Excess of Risk-Increasing Low-Frequency Variants Can Be a Signal of Polygenic Inheritance in Complex Diseases

Yingleong Chan, Elaine T. Lim, Niina Sandholm, Sophie R. Wang, Amy Jayne McKnight, Stephan Ripke, Mark J. Daly, Benjamin M. Neale, Rany M. Salem, Joel N. Hirschhorn

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)437-452
Number of pages16
JournalThe American Journal of Human Genetics
Volume94
Issue number3
DOIs
Publication statusPublished - 06 Mar 2014

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Multifactorial Inheritance
Genome-Wide Association Study
Ulcerative Colitis
Crohn Disease
Chronic Kidney Failure
Phenotype
Diabetic Nephropathies
Inflammatory Bowel Diseases
Sample Size
Type 2 Diabetes Mellitus
Schizophrenia
Odds Ratio
Population

Cite this

Chan, Yingleong ; Lim, Elaine T. ; Sandholm, Niina ; Wang, Sophie R. ; McKnight, Amy Jayne ; Ripke, Stephan ; Daly, Mark J. ; Neale, Benjamin M. ; Salem, Rany M. ; Hirschhorn, Joel N. / An Excess of Risk-Increasing Low-Frequency Variants Can Be a Signal of Polygenic Inheritance in Complex Diseases. In: The American Journal of Human Genetics. 2014 ; Vol. 94, No. 3. pp. 437-452.
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Chan, Y, Lim, ET, Sandholm, N, Wang, SR, McKnight, AJ, Ripke, S, Daly, MJ, Neale, BM, Salem, RM & Hirschhorn, JN 2014, 'An Excess of Risk-Increasing Low-Frequency Variants Can Be a Signal of Polygenic Inheritance in Complex Diseases', The American Journal of Human Genetics, vol. 94, no. 3, pp. 437-452. https://doi.org/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. / Chan, Yingleong; Lim, Elaine T.; Sandholm, Niina; Wang, Sophie R.; McKnight, Amy Jayne; Ripke, Stephan; Daly, Mark J.; Neale, Benjamin M.; Salem, Rany M.; Hirschhorn, Joel N.

In: The American Journal of Human Genetics, Vol. 94, No. 3, 06.03.2014, p. 437-452.

Research output: Contribution to journalArticle

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AU - Chan, Yingleong

AU - Lim, Elaine T.

AU - Sandholm, Niina

AU - Wang, Sophie R.

AU - McKnight, Amy Jayne

AU - Ripke, Stephan

AU - Daly, Mark J.

AU - Neale, Benjamin M.

AU - Salem, Rany M.

AU - Hirschhorn, Joel N.

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AB - 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.

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