Evaluating the contribution of rare variants to type 2 diabetes and related traits using pedigrees
Jun G., Manning A., Almeida M., Zawistowski M., Wood AR., Teslovich TM., Fuchsberger C., Feng S., Cingolani P., Gaulton KJ., Dyer T., Blackwell TW., Chen H., Chines PS., Choi S., Churchhouse C., Fontanillas P., King R., Lee S., Lincoln SE., Trubetskoy V., DePristo M., Fingerlin T., Grossman R., Grundstad J., Heath A., Kim J., Kim YJ., Laramie J., Lee J., Li H., Liu X., Livne O., Locke AE., Maller J., Mazur A., Morris AP., Pollin TI., Ragona D., Reich D., Rivas MA., Scott LJ., Sim X., Tearle RG., Teo YY., Williams AL., Zöllner S., Curran JE., Peralta J., Akolkar B., Bell GI., Burtt NP., Cox NJ., Florez JC., Hanis CL., McKeon C., Mohlke KL., Seielstad M., Wilson JG., Atzmon G., Below JE., Dupuis J., Nicolae DL., Lehman D., Park T., Won S., Sladek R., Altshuler D., McCarthy MI., Duggirala R., Boehnke M., Frayling TM., Abecasis GR., Blangero J.
Significance Contributions of rare variants to common and complex traits such as type 2 diabetes (T2D) are difficult to measure. This paper describes our results from deep whole-genome analysis of large Mexican-American pedigrees to understand the role of rare-sequence variations in T2D and related traits through enriched allele counts in pedigrees. Our study design was well-powered to detect association of rare variants if rare variants with large effects collectively accounted for large portions of risk variability, but our results did not identify such variants in this sample. We further quantified the contributions of common and rare variants in gene expression profiles and concluded that rare expression quantitative trait loci explain a substantive, but minor, portion of expression heritability.