Investigating the role of commoncis-regulatory variants in modifying penetrance of putatively damaging, inherited variants in severe neurodevelopmental disorders

Abstract

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 6,987 probands from the Deciphering Developmental Disorders (DDD) study and 9,720 controls, and found one gene,RAB2A, that passed multiple testing correction (p = 6.7×10-7). We then investigated whethercis-eQTLs modify the penetrance of putatively damaging, rare coding variants inherited by NDD probands from their unaffected parents in a set of 1,700 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 commoncis-eQTLs modify penetrance of rare coding variants in a large cohort of NDD probands.

Exploring penetrance of clinically relevant variants in over 800,000 humans from the Genome Aggregation Database

“…Previous studies of disease-variants present in population databases have focused on descriptive reports 1 , statistical associations between disease-variants and phenotypes 8–10,14,30 , estimated penetrance of specific disorders 8,9,31 , gene-specific mechanisms 15 or a specific type of modifying variants (e.g. eQTLs/ sQTLs) 16,18,32 . We aimed to move beyond previous efforts by using a large-scale but non-statistical approach, under the hypothesis that some of these modes are rare and need in-depth investigation of the relevant region to allow discovery of the underlying reason for the lack of disease manifestation.…”

“…Investigations moving beyond descriptive reports and association studies towards focusing on mechanisms underlying incomplete penetrance are few and disease-specific [11][12][13][14] , with examples of how expression levels 15 , eQTL 16 , and sQTLs 17 could modulate penetrance. A statistical approach to investigate eQTL association with incomplete penetrance in neurodevelopmental disease in 1,700 trios from the Deciphering Developmental Disorder cohort did not find altered gene expression due to known eQTLs to be an explanation for incomplete penetrance in the unaffected parents carrying the variant of the affected probands 18 .…”

Genetic modifiers of rare variants in monogenic developmental disorder loci

“…It has previously been shown that rare predicted loss-of-function (pLoF) variants, as well as deleterious missense and large copy number variants (CNVs), in genes and loci linked with severe monogenic developmental disorders (DDs) can have milder, subclinical effects in the general population 14,[22][23][24][25] . The related common variant burden has been shown to affect the phenotype in carriers of such variants 5,26 , suggesting that the cumulative effect of common variants can modify the penetrance of rare variants in such phenotypes, even when the primary cause is considered monogenic.…”