title: An excess of risk-increasing low-frequency variants can be a signal of polygenic inheritance in complex diseases.
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.
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Department of Endocrinology, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Yingleong
authors.initials: Y
authors.lastname: Chan
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, MA 02114, USA.
authors.forename: Elaine T
authors.initials: ET
authors.lastname: Lim
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki 00290, Finland; Division of Nephrology, Department of Medicine, Helsinki University Central Hospital, Helsinki 00290, Finland; Department of Biomedical Engineering and Computational Science, Aalto University School of Science, Helsinki 00076, Finland.
authors.forename: Niina
authors.initials: N
authors.lastname: Sandholm
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Department of Endocrinology, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Sophie R
authors.initials: SR
authors.lastname: Wang
authors.affiliation: Nephrology Research, Centre for Public Health, Queen's University of Belfast, Belfast, Northern Ireland BT7 1NN, UK.
authors.forename: Amy Jayne
authors.initials: AJ
authors.lastname: McKnight
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, MA 02114, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ripke
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, MA 02114, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, MA 02114, USA.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Neale
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Department of Endocrinology, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Rany M
authors.initials: RM
authors.lastname: Salem
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Department of Endocrinology, Boston Children's Hospital, Boston, MA 02115, USA. Electronic address: joelh@broadinstitute.org.
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
mesh_terms: D000419:Albuminuria / Q000235:genetics; D003093:Colitis, Ulcerative / Q000235:genetics*; D003424:Crohn Disease / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D003928:Diabetic Nephropathies / Q000235:genetics; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D007676:Kidney Failure, Chronic / Q000235:genetics; D001523:Mental Disorders / Q000235:genetics; D015233:Models, Statistical; D020412:Multifactorial Inheritance; D009765:Obesity / Q000235:genetics; D016017:Odds Ratio; D010641:Phenotype; D012306:Risk