Deviation from baseline mutation burden provides powerful and robust rare-variants association test for complex diseases

Lin Jiang, Hui Jiang, Sheng Dai, Ying Chen, Youqiang Song, Clara Sze Man Tang, Shirley Yin Yu Pang, Shu Leong Ho, Binbin Wang, Maria Mercedes Garcia-Barcelo, Paul Kwong Hang Tam, Stacey S. Cherny, Mulin Jun Li, Pak Chung Sham*, Miaoxin Li*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Identifying rare variants that contribute to complex diseases is challenging because of the low statistical power in current tests comparing cases with controls. Here, we propose a novel and powerful rare variants association test based on the deviation of the observed mutation burden of a gene in cases from a baseline predicted by a weighted recursive truncated negative-binomial regression (RUNNER) on genomic features available from public data. Simulation studies show that RUNNER is substantially more powerful than state-of-the-art rare variant association tests and has reasonable type 1 error rates even for stratified populations or in small samples. Applied to real case-control data, RUNNER recapitulates known genes of Hirschsprung disease and Alzheimer's disease missed by current methods and detects promising new candidate genes for both disorders. In a case-only study, RUNNER successfully detected a known causal gene of amyotrophic lateral sclerosis. The present study provides a powerful and robust method to identify susceptibility genes with rare risk variants for complex diseases.

Original languageEnglish
Pages (from-to)E34
JournalNucleic Acids Research
Issue number6
StatePublished - 8 Apr 2022


FundersFunder number
Guangdong projectT12-704/16-R, T12C-714/14-R, 2017GC010644, T12- 701/17-R
National Natural Science Foundation of China31970650, 31771401
Guangzhou Science and Technology Program key projects201803010116
National Key Research and Development Program of China2016YFC0904300, 2018YFC0910500


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