The article "The Genetic Architecture of Type 2 Diabetes" by Fuchsberger et al. (2016) explores the genetic factors contributing to the risk of type 2 diabetes (T2D). The study combines data from the GoT2D and T2D-GENES consortia, which performed whole genome sequencing and exome sequencing in large cohorts of Europeans with and without T2D. The authors aimed to identify common and low-frequency variants associated with T2D risk and to assess the contribution of these variants to the heritability of the disease. Key findings include: - Common variants identified by genome-wide association studies (GWAS) explain only a fraction of the heritability of T2D. - Whole genome sequencing identified 126 variants at four loci associated with T2D, most of which were common. - Exome sequencing identified one variant (PAX4 Arg192His) associated with T2D risk, which was specific to East Asians. - Gene-based tests for rare-variant associations in monogenic and syndromic diabetes genes showed weak aggregate association with T2D risk. - Synthetic associations, where common-variant GWAS signals are explained by low-frequency and rare variants, were not detected in the studied loci. The study concludes that while low-frequency variants may play a role in T2D risk, they do not contribute significantly to the heritability of the disease compared to common variants. The findings highlight the importance of understanding the genetic architecture of complex traits and the need for further research to identify the mechanisms by which common and rare variants influence disease risk.The article "The Genetic Architecture of Type 2 Diabetes" by Fuchsberger et al. (2016) explores the genetic factors contributing to the risk of type 2 diabetes (T2D). The study combines data from the GoT2D and T2D-GENES consortia, which performed whole genome sequencing and exome sequencing in large cohorts of Europeans with and without T2D. The authors aimed to identify common and low-frequency variants associated with T2D risk and to assess the contribution of these variants to the heritability of the disease. Key findings include: - Common variants identified by genome-wide association studies (GWAS) explain only a fraction of the heritability of T2D. - Whole genome sequencing identified 126 variants at four loci associated with T2D, most of which were common. - Exome sequencing identified one variant (PAX4 Arg192His) associated with T2D risk, which was specific to East Asians. - Gene-based tests for rare-variant associations in monogenic and syndromic diabetes genes showed weak aggregate association with T2D risk. - Synthetic associations, where common-variant GWAS signals are explained by low-frequency and rare variants, were not detected in the studied loci. The study concludes that while low-frequency variants may play a role in T2D risk, they do not contribute significantly to the heritability of the disease compared to common variants. The findings highlight the importance of understanding the genetic architecture of complex traits and the need for further research to identify the mechanisms by which common and rare variants influence disease risk.