The Effect of Phenotypic Outliers and Non-normality on Rare-variant Association Testing

Overview

Journal Eur J Hum Genet

Specialty Genetics

Date 2016 Jan 7

PMID 26733287

Citations 21

Authors

Paul L Auer

Alex P Reiner

Suzanne M Leal

Affiliations

Soon will be listed here.

Abstract

Rare-variant association studies (RVAS) have made important contributions to human complex trait genetics. These studies rely on specialized statistical methods for analyzing rare-variant associations, both individually and in aggregate. We investigated the impact that phenotypic outliers and non-normality have on the performance of rare-variant association testing procedures. Ignoring outliers or non-normality can significantly inflate Type I error rates. We found that rank-based inverse normal transformation (INT) and trait winsorisation were both effective at maintaining Type I error control without sacrificing power in the presence of outliers. INT was the optimal method for non-normally distributed traits. For RVAS of quantitative traits with outliers or non-normality, we recommend using INT to transform phenotypic values before association testing.

Citing Articles

Sex disparities in the association between rare earth elements exposure and genetic mutation frequencies in lung cancer patients.

Liu M, Zhang J, Duan X, Zhou Q, Chen J, Liu S Sci Rep. 2025; 15(1):2185.

PMID: 39820492 PMC: 11739476. DOI: 10.1038/s41598-024-79580-z.

Disentangling the consequences of type 2 diabetes on targeted metabolite profiles using causal inference and interaction QTL analyses.

Bocher O, Singh A, Huang Y, Vosa U, Reimann E, Arruda A PLoS Genet. 2024; 20(12):e1011346.

PMID: 39625957 PMC: 11642953. DOI: 10.1371/journal.pgen.1011346.

Polymorphic short tandem repeats make widespread contributions to blood and serum traits.

Margoliash J, Fuchs S, Li Y, Zhang X, Massarat A, Goren A Cell Genom. 2023; 3(12):100458.

PMID: 38116119 PMC: 10726533. DOI: 10.1016/j.xgen.2023.100458.

Gene-based association study of rare variants in children of diverse ancestries implicates TNFRSF21 in the development of allergic asthma.

Clay S, Alladina J, Smith N, Visness C, Wood R, OConnor G J Allergy Clin Immunol. 2023; 153(3):809-820.

PMID: 37944567 PMC: 10939893. DOI: 10.1016/j.jaci.2023.10.023.

Multivariate GWAS of Alzheimer's disease CSF biomarker profiles implies GRIN2D in synaptic functioning.

Neumann A, Ohlei O, Kucukali F, Bos I, Timsina J, Vos S Genome Med. 2023; 15(1):79.

PMID: 37794492 PMC: 10548686. DOI: 10.1186/s13073-023-01233-z.

References

Logsdon B, Dai J, Auer P, Johnsen J, Ganesh S, Smith N . A variational Bayes discrete mixture test for rare variant association. Genet Epidemiol. 2014; 38(1):21-30. PMC: 4030763. DOI: 10.1002/gepi.21772. View

Beasley T, Erickson S, Allison D . Rank-based inverse normal transformations are increasingly used, but are they merited?. Behav Genet. 2009; 39(5):580-95. PMC: 2921808. DOI: 10.1007/s10519-009-9281-0. View

Morris A, Zeggini E . An evaluation of statistical approaches to rare variant analysis in genetic association studies. Genet Epidemiol. 2009; 34(2):188-93. PMC: 2962811. DOI: 10.1002/gepi.20450. View

Price A, Kryukov G, de Bakker P, Purcell S, Staples J, Wei L . Pooled association tests for rare variants in exon-resequencing studies. Am J Hum Genet. 2010; 86(6):832-8. PMC: 3032073. DOI: 10.1016/j.ajhg.2010.04.005. View

Schick U, Auer P, Bis J, Lin H, Wei P, Pankratz N . Association of exome sequences with plasma C-reactive protein levels in >9000 participants. Hum Mol Genet. 2014; 24(2):559-71. PMC: 4334838. DOI: 10.1093/hmg/ddu450. View

Auer P, Teumer A, Schick U, OShaughnessy A, Lo K, Chami N . Rare and low-frequency coding variants in CXCR2 and other genes are associated with hematological traits. Nat Genet. 2014; 46(6):629-34. PMC: 4050975. DOI: 10.1038/ng.2962. View

. Design of the Women's Health Initiative clinical trial and observational study. The Women's Health Initiative Study Group. Control Clin Trials. 1998; 19(1):61-109. DOI: 10.1016/s0197-2456(97)00078-0. View

Lin D, Tang Z . A general framework for detecting disease associations with rare variants in sequencing studies. Am J Hum Genet. 2011; 89(3):354-67. PMC: 3169821. DOI: 10.1016/j.ajhg.2011.07.015. View

Peloso G, Auer P, Bis J, Voorman A, Morrison A, Stitziel N . Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks. Am J Hum Genet. 2014; 94(2):223-32. PMC: 3928662. DOI: 10.1016/j.ajhg.2014.01.009. View

10.

Crosby J, Peloso G, Auer P, Crosslin D, Stitziel N, Lange L . Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med. 2014; 371(1):22-31. PMC: 4180269. DOI: 10.1056/NEJMoa1307095. View

11.

Che R, Motsinger-Reif A, Brown C . Loss of power in two-stage residual-outcome regression analysis in genetic association studies. Genet Epidemiol. 2012; 36(8):890-4. PMC: 4350584. DOI: 10.1002/gepi.21671. View

12.

Huyghe J, Jackson A, Fogarty M, Buchkovich M, Stancakova A, Stringham H . Exome array analysis identifies new loci and low-frequency variants influencing insulin processing and secretion. Nat Genet. 2012; 45(2):197-201. PMC: 3727235. DOI: 10.1038/ng.2507. View

13.

Do R, Stitziel N, Won H, Jorgensen A, Duga S, Merlini P . Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature. 2014; 518(7537):102-6. PMC: 4319990. DOI: 10.1038/nature13917. View

14.

Buzkova P . Linear regression in genetic association studies. PLoS One. 2013; 8(2):e56976. PMC: 3578817. DOI: 10.1371/journal.pone.0056976. View

15.

Lange L, Hu Y, Zhang H, Xue C, Schmidt E, Tang Z . Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol. Am J Hum Genet. 2014; 94(2):233-45. PMC: 3928660. DOI: 10.1016/j.ajhg.2014.01.010. View

16.

Manolio T, Collins F, Cox N, Goldstein D, Hindorff L, Hunter D . Finding the missing heritability of complex diseases. Nature. 2009; 461(7265):747-53. PMC: 2831613. DOI: 10.1038/nature08494. View

17.

Reiner A, Lettre G, Nalls M, Ganesh S, Mathias R, Austin M . Genome-wide association study of white blood cell count in 16,388 African Americans: the continental origins and genetic epidemiology network (COGENT). PLoS Genet. 2011; 7(6):e1002108. PMC: 3128101. DOI: 10.1371/journal.pgen.1002108. View

18.

Auer P, Wang G, Leal S . Testing for rare variant associations in the presence of missing data. Genet Epidemiol. 2013; 37(6):529-38. PMC: 4459641. DOI: 10.1002/gepi.21736. View

19.

Demissie S, Cupples L . Bias due to two-stage residual-outcome regression analysis in genetic association studies. Genet Epidemiol. 2011; 35(7):592-6. PMC: 3201714. DOI: 10.1002/gepi.20607. View

20.

Wu M, Lee S, Cai T, Li Y, Boehnke M, Lin X . Rare-variant association testing for sequencing data with the sequence kernel association test. Am J Hum Genet. 2011; 89(1):82-93. PMC: 3135811. DOI: 10.1016/j.ajhg.2011.05.029. View