biostudies-literatureLin XNational Institute of Environmental Health SciencesNIEHS NIH HHSNHLBI NIH HHSNational Cancer InstituteNCI NIH HHSNational Institutes of HealthPHS HHS156-64https://www.ebi.ac.uk/biostudies/studies/S-EPMC4733434biostudies-literatureUnknown72(1)We consider in this article testing rare variants by environment interactions in sequencing association studies. Current methods for studying the association of rare variants with traits cannot be readily applied for testing for rare variants by environment interactions, as these methods do not effectively control for the main effects of rare variants, leading to unstable results and/or inflated Type 1 error rates. We will first analytically study the bias of the use of conventional burden-based tests for rare variants by environment interactions, and show the tests can often be invalid and result in inflated Type 1 error rates. To overcome these difficulties, we develop the interaction sequence kernel association test (iSKAT) for assessing rare variants by environment interactions. The prBiometricsTest for rare variants by environment interactions in sequencing association studies.PMC4733434P01 CA134294R00HL113164P30 ES000002R35 CA197449R37 CA076404P42-ES016454R00H L113164R37-CA076404R01 HL113338T32 ES007142P42 ES016454P01-CA134294R00 HL113164Lee SLi ZWang CWu MCLin XChen HfalseTest for rare variants by environment interactions in sequencing association studies.We consider in this article testing rare variants by environment interactions in sequencing association studies. Current methods for studying the association of rare variants with traits cannot be readily applied for testing for rare variants by environment interactions, as these methods do not effectively control for the main effects of rare variants, leading to unstable results and/or inflated Type 1 error rates. We will first analytically study the bias of the use of conventional burden-based tests for rare variants by environment interactions, and show the tests can often be invalid and result in inflated Type 1 error rates. To overcome these difficulties, we develop the interaction sequence kernel association test (iSKAT) for assessing rare variants by environment interactions. The pr2016-01-01T00:00:00Z2016 Mar2026-05-05T07:13:34.291Z2019-03-27T02:07:54ZS-EPMC47334342622904710.1111/biom.12368