Investigating the role of common cis-regulatory variants in modifying penetrance of putatively damaging, inherited variants in severe neurodevelopmental disorders
This is the final version. Available on open access from Nature Research via the DOI in this record. Data availability: The DDD data are available in the European Genome-Phenome Archive (EGA). These include the exome sequence data (EGAD00001004389), phenotypic and family descriptions (EGAD00001004388), CoreExome array data (EGAD00010001598, EGAD00010001600, EGAD00010001604) and Global Screening Array data (first batch raw data: EGAD00010002567, second batch raw data, EGAD00010002569 and QCed data: EGAD00010002568). The UKHLS genotype data are also available on EGA (EGAS00001001232).Recent work has revealed an important role for rare, incompletely penetrant inherited coding variants in neurodevelopmental disorders (NDDs). Additionally, we have previously shown that common variants contribute to risk for rare NDDs. Here, we investigate whether common variants exert their effects by modifying gene expression, using multi-cis-expression quantitative trait loci (cis-eQTL) prediction models. We first performed a transcriptome-wide association study for NDDs using 6987 probands from the Deciphering Developmental Disorders (DDD) study and 9720 controls, and found one gene, RAB2A, that passed multiple testing correction (p = 6.7 × 10-7). We then investigated whether cis-eQTLs modify the penetrance of putatively damaging, rare coding variants inherited by NDD probands from their unaffected parents in a set of 1700 trios. We found no evidence that unaffected parents transmitting putatively damaging coding variants had higher genetically-predicted expression of the variant-harboring gene than their child. In probands carrying putatively damaging variants in constrained genes, the genetically-predicted expression of these genes in blood was lower than in controls (p = 2.7 × 10-3). However, results for proband-control comparisons were inconsistent across different sets of genes, variant filters and tissues. We find limited evidence that common cis-eQTLs modify penetrance of rare coding variants in a large cohort of NDD probands.Health Innovation Challenge FundWellcome Sanger InstituteWellcome Trus
