RT Journal Article SR Electronic T1 De novo mutations implicate novel genes with burden of rare variants in Systemic Lupus Erythematosus JF bioRxiv FD Cold Spring Harbor Laboratory SP 139238 DO 10.1101/139238 A1 Venu Pullabhatla A1 Amy L. Roberts A1 Myles J. Lewis A1 Daniele Mauro A1 David L. Morris A1 Christopher A. Odhams A1 Philip Tombleson A1 Ulrika Liljedahl A1 Simon Vyse A1 Michael A. Simpson A1 Sascha Sauer A1 Emanuele de Rinaldis A1 Ann-Christine Syvänen A1 Timothy J. Vyse YR 2017 UL http://biorxiv.org/content/early/2017/05/17/139238.abstract AB The heritability of most complex diseases, including autoimmune disease Systemic Lupus Erythematosus (SLE), remains largely unexplained by common variation, and few examples of rare variant associations have been identified. Here, using complementary whole-exome sequencing (WES) and high-density imputation, we identify candidate genes through de novo mutation discovery and demonstrate collective rare variant associations at novel SLE-susceptibility genes. Using extreme-phenotype sampling, we sequenced the exomes of 30 SLE parent-affected-offspring trios and identified 14 genes with missense de novo mutations, none of which are within the >70 SLE susceptibility loci implicated through genome-wide association studies (GWAS). In a follow-up cohort of 10,995 individuals of matched European ancestry, including 4,036 SLE cases, we imputed genotype data to the density of the combined UK10K-1000 genomes Phase III reference panel across the 14 candidate genes. We identify a burden of rare exonic variants across PRKCD associated with SLE risk (P=0.0028), and across DNMT3A associated with two severe disease prognosis sub-phenotypes (P=0.0005 and P=0.0033). Additionally, we show the p.His198Gln de novo mutation within the candidate gene C1QTNF4 inhibits NF-κB activation following TNF exposure. Exome sequencing studies typically lack power to detect rare variant associations for complex traits. Our results support extreme-phenotype sampling and using de novo mutation gene discovery to aid the search for rare variation contributing to the heritability of complex diseases.