Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes

Abstract

Through whole-genome sequencing of 2,630 Icelanders and imputation into 11,114 Icelandic cases and 267,140 controls followed by testing in Danish and Iranian samples, we discovered 4 previously unreported variants affecting risk of type 2 diabetes (T2D). A low-frequency (1.47%) variant in intron 1 of CCND2, rs76895963[G], reduces risk of T2D by half (odds ratio (OR) = 0.53, P = 5.0 × 10(-21)) and is correlated with increased CCND2 expression. Notably, this variant is also associated with both greater height and higher body mass index (1.17 cm per allele, P = 5.5 × 10(-12) and 0.56 kg/m(2) per allele, P = 6.5 × 10(-7), respectively). In addition, two missense variants in PAM, encoding p.Asp563Gly (frequency of 4.98%) and p.Ser539Trp (frequency of 0.65%), confer moderately higher risk of T2D (OR = 1.23, P = 3.9 × 10(-10) and OR = 1.47, P = 1.7 × 10(-5), respectively), and a rare (0.20%) frameshift variant in PDX1, encoding p.Gly218Alafs*12, associates with high risk of T2D (OR = 2.27, P = 7.3 × 10(-7)).

10 Years of GWAS Discovery: Biology, Function, and Translation

“…[74][75][76] Recent efforts to extend GWASs beyond arraybased genotyping and to access a broader range of variants through sequencing (particularly those of lower frequency) have revealed that most genetic variation influencing T2D appears to reside at common variant sites. 74,77 This chimes with the view of T2D as a largely post-reproductive trait and is consistent with a failure to detect compelling empirical evidence that T2D risk alleles have been subject to marked purifying selection. 78,79 In keeping with the age of these common risk alleles (which predates the diaspora of modern humans out of Africa), most common variant associations for T2D are replicated across major ethnic groups.…”

Genetic architecture of type 2 diabetes

“…1b). This included two previously-reported common-variant loci (TCF7L2, ADCY5), a previously-reported lowfrequency variant in CCND2 7 (rs76895963, MAF=2.6%, p seq =4.2×10 −9 ), and a novel common-variant association near EML4 (MAF=34.8%, p seq =1.0×10 −8 ). There was no significant evidence of T2D association for sets of low-frequency or rare variants within coding regions, nor within specified non-coding regulatory elements (Methods).…”

“…Over the past decade, successive waves of T2D GWAS -featuring ever larger samples, progressively denser genotyping arrays supplemented by imputation against more complete reference panels, and richer ethnic diversity -have delivered >80 robust association signals [2][3][4][5][6][7][8] . However, in these studies, the alleles interrogated for association are predominantly common (minor allele frequency [MAF]>5%), and with limited exceptions 7,9 , the variants driving known association signals are also common, with individually-modest impacts on T2D risk [2][3][4][5][6][7][8]10 . Variation at known loci explains only a minority of observed T2D heritability 2,3,11 .…”

“…However, the contribution to T2D risk attributable to lower-frequency variants remains a matter of considerable debate, not least because of the relevance of disease architecture to clinical application 11 . Next-generation sequencing enables direct evaluation of the role of lower-frequency variants to disease risk 7,12,13 . This paper describes the efforts of the coordinated, complementary strategies pursued by the Genetics of Type 2 Diabetes (GoT2D) and T2D-GENES (Type 2 Diabetes Genetic Exploration by Next-generation sequencing in multi-Ethnic Samples) Consortia.…”

VariantASGR1Associated with a Reduced Risk of Coronary Artery Disease

“…Details regarding the population sample sets from Iceland, Denmark, and the Netherlands that were used to measure the various lipid traits (non-HDL cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides), alkaline phosphatase, and vitamin B 12 are provided in the Methods section and Table S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org. Details regarding the 10 casecontrol sample sets are provided in the Methods section and Table S2 in the Supplementary Appendix.…”