%0 Journal Article %A Vijay Kumar Pounraja %A Santhosh Girirajan %T A general framework for identifying rare variant combinations in complex disorders %D 2021 %R 10.1101/2021.10.01.462832 %J bioRxiv %P 2021.10.01.462832 %X Statistical challenges due to rarity and combinatorial explosion resulting from exhaustive evaluation of rare variant combinations have limited the study of oligogenic etiology for complex disorders. We present RareComb, a framework that combines apriori algorithm and statistical inference to identify specific combinations of mutated genes associated with complex phenotypes. Using RareComb on 6,189 affected individuals, we identified 718 combinations of mutated genes significantly associated with intellectual disability (ID), and carriers of these combinations showed lower IQ than expected in a replication cohort of 1,878 individuals. These combinations were enriched for nervous system genes, showed complex inheritance patterns, and were depleted in unaffected siblings. We further identified oligogenic combinations associated with multiple comorbid phenotypes, including COL28A1 and MFSD2B mutations for ID and schizophrenia. Our framework enables rare variant analysis in affected individuals lacking diagnosis based on de novo mutations, and provides a paradigm for dissecting the genetic basis of complex disorders.Competing Interest StatementThe authors have declared no competing interest. %U https://www.biorxiv.org/content/biorxiv/early/2021/10/01/2021.10.01.462832.full.pdf