Rare and common variant discovery in complex disease: the IBD case study.
Human molecular genetics
Complex diseases such as inflammatory bowel disease (IBD), which consists of ulcerative colitis and Crohn's disease, are a significant medical burden - 70,000 new cases of IBD are diagnosed in the United States annually. In this Review, we examine the history of genetic variant discovery in complex disease with a focus on IBD. We cover methods that have been applied to microsatellite, common variant, targeted resequencing, and whole-exome and -genome data, specifically focusing on the progression of technologies towards rare-variant discovery. The inception of these methods combined with better availability of population level variation data has led to rapid discovery of IBD-causative and/or -associated variants at over 200 loci; over time, these methods have grown exponentially in both power and ascertainment to detect rare variation. We highlight rare-variant discoveries critical to the elucidation of the pathogenesis of IBD, including those in NOD2, IL23R, CARD9, RNF186, and ADCY7. We additionally identify the major areas of rare-variant discovery that will evolve in the coming years. A better understanding of the genetic basis of IBD and other complex diseases will lead to improved diagnosis, prognosis, treatment, and surveillance.
View details for DOI 10.1093/hmg/ddz189
View details for PubMedID 31363759
DE NOVO MUTATIONS IN AUTISM IMPLICATE THE SYNAPTIC ELIMINATION NETWORK.
Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing
2016; 22: 521-532
Autism has been shown to have a major genetic risk component; the architecture of documented autism in families has been over and again shown to be passed down for generations. While inherited risk plays an important role in the autistic nature of children, de novo (germline) mutations have also been implicated in autism risk. Here we find that autism de novo variants verified and published in the literature are Bonferroni-significantly enriched in a gene set implicated in synaptic elimination. Additionally, several of the genes in this synaptic elimination set that were enriched in protein-protein interactions (CACNA1C, SHANK2, SYNGAP1, NLGN3, NRXN1, and PTEN) have been previously confirmed as genes that confer risk for the disorder. The results demonstrate that autism-associated de novos are linked to proper synaptic pruning and density, hinting at the etiology of autism and suggesting pathophysiology for downstream correction and treatment.
View details for PubMedID 27897003