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Cohort-wide deep whole genome sequencing and the allelic architecture of complex traits.

Arthur GillyDaniel SuvegesKaroline KuchenbaeckerMartin O PollardLorraine SouthamKonstantinos HatzikotoulasAliki-Eleni FarmakiThea BjornlandRyan WaplesEmil Vincent R AppelElisabetta CasaloneGiorgio E M MelloniBritt KilianNigel W RaynerIoanna NtallaKousik KunduKlaudia WalterJohn DaneshAdam S ButterworthInês A BarrosoEmmanouil TsafantakisGeorge DedoussisIda MoltkeEleftheria Zeggini
Published in: Nature communications (2018)
The role of rare variants in complex traits remains uncharted. Here, we conduct deep whole genome sequencing of 1457 individuals from an isolated population, and test for rare variant burdens across six cardiometabolic traits. We identify a role for rare regulatory variation, which has hitherto been missed. We find evidence of rare variant burdens that are independent of established common variant signals (ADIPOQ and adiponectin, P = 4.2 × 10-8; APOC3 and triglyceride levels, P = 1.5 × 10-26), and identify replicating evidence for a burden associated with triglyceride levels in FAM189B (P = 2.2 × 10-8), indicating a role for this gene in lipid metabolism.
Keyphrases
  • genome wide
  • copy number
  • metabolic syndrome
  • dna methylation
  • type diabetes
  • skeletal muscle
  • insulin resistance
  • fatty acid
  • genome wide identification