The majority of reported complex disease associations for common genetic variants have been identified through meta-analysis, a powerful approach that enables the use of large sample sizes while protecting against common artifacts due to population structure and repeated small-sample analyses sharing individual-level data. As the focus of genetic association studies shifts to rare variants, genes and other functional units are becoming the focus of analysis. Here we propose and evaluate new approaches for performing meta-analysis of rare variant association tests, including burden tests, weighted burden tests, variable-threshold tests and tests that allow variants with opposite effects to be grouped together. We show that our approach retains useful features from single-variant meta-analysis approaches and demonstrate its use in a study of blood lipid levels in ∼18,500 individuals genotyped with exome arrays.
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The authors would like to thank M. Boehnke, X. Wen and S. Zoellner for helpful discussions. This work was supported by research grants R01HG007022 from the National Human Genome Research Institute, R01EY022005 from the National Eye Institute and R01HL117626 from the National Heart, Lung, and Blood Institute. G.M.P. was supported by award T32HL007208 from the National Heart, Lung, and Blood Institute. S.K. is supported by a Research Scholar award from Massachusetts General Hospital (MGH), the Howard Goodman Fellowship from MGH, the Donovan Family Foundation and grant R01HL107816 from the National Heart, Lung, and Blood Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the US National Institutes of Health. The WHI program is funded by the National Heart, Lung, and Blood Institute, US National Institutes of Health, US Department of Health and Human Services through contracts N01WH22110, N01WH24152, N01WH32100-2, N01WH32105-6, N01WH32108-9, N01WH32111-13, N01WH32115, N01WH32118-32119, N01WH32122, N01WH42107-26, N01WH42129-32 and N01WH44221. This manuscript was prepared in collaboration with investigators from the WHI and has been approved by the WHI. WHI investigators are listed at https://cleo.whi.org/researchers/SitePages/WHI%20Investigators.aspx. The full list of PROCARDIS acknowledgments is available at http://www.procardis.org/. The Ottawa Heart Genomics Study was supported by Canadian Institutes of Health Research (CIHR) grants MOP-82810, MOP-77682 and MOP-2380941 and Canada Foundation for Innovation (CFI) grant 11966. The studies for the Malmö Diet and Cancer cohort were supported by grants from the Swedish Research Council, the Swedish Heart and Lung Foundation, the Påhlsson Foundation, the Novo Nordic Foundation and European Research Council starting grant StG-282255.
Supplementary Figures 1–15, Supplementary Tables 1–12 and Supplementary Note