The genetic architecture of type 2 diabetes (T2D) was investigated using whole-genome and exome sequencing in 2,657 Europeans with and without T2D, and exome sequencing in 12,940 individuals from five ancestral groups. The study aimed to determine whether low-frequency or rare variants contribute significantly to T2D risk. Genome-wide association studies (GWAS) have identified many common variants associated with T2D, but these explain only a fraction of heritability. The study found that most variants associated with T2D were common and fell within regions previously identified by GWAS. Comprehensive sequencing did not support a major role for low-frequency variants in T2D predisposition. The study also identified several common variants associated with T2D, including those near EML4 and CENPW. Conditional analysis identified two novel association signals involving low-frequency variants. The study also analyzed coding variation and found that rare variants in genes like PAX4 were associated with T2D. The study did not find evidence for synthetic associations between common and low-frequency variants. The results suggest that common variants explain most of T2D heritability, and that low-frequency variants contribute less. The study also identified several candidate functional alleles, including those in genes like TM6SF2 and RREB1. The study highlights the importance of understanding the genetic architecture of T2D for developing precision medicine approaches. The study was conducted using a combination of sequencing and genotyping data, and the results were validated in independent cohorts. The study provides insights into the genetic basis of T2D and the role of rare variants in disease risk. The findings suggest that common variants are the primary contributors to T2D heritability, and that rare variants have a limited role. The study also emphasizes the importance of large-scale sequencing in identifying functional alleles and understanding the genetic architecture of complex diseases.The genetic architecture of type 2 diabetes (T2D) was investigated using whole-genome and exome sequencing in 2,657 Europeans with and without T2D, and exome sequencing in 12,940 individuals from five ancestral groups. The study aimed to determine whether low-frequency or rare variants contribute significantly to T2D risk. Genome-wide association studies (GWAS) have identified many common variants associated with T2D, but these explain only a fraction of heritability. The study found that most variants associated with T2D were common and fell within regions previously identified by GWAS. Comprehensive sequencing did not support a major role for low-frequency variants in T2D predisposition. The study also identified several common variants associated with T2D, including those near EML4 and CENPW. Conditional analysis identified two novel association signals involving low-frequency variants. The study also analyzed coding variation and found that rare variants in genes like PAX4 were associated with T2D. The study did not find evidence for synthetic associations between common and low-frequency variants. The results suggest that common variants explain most of T2D heritability, and that low-frequency variants contribute less. The study also identified several candidate functional alleles, including those in genes like TM6SF2 and RREB1. The study highlights the importance of understanding the genetic architecture of T2D for developing precision medicine approaches. The study was conducted using a combination of sequencing and genotyping data, and the results were validated in independent cohorts. The study provides insights into the genetic basis of T2D and the role of rare variants in disease risk. The findings suggest that common variants are the primary contributors to T2D heritability, and that rare variants have a limited role. The study also emphasizes the importance of large-scale sequencing in identifying functional alleles and understanding the genetic architecture of complex diseases.