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We carried out a genome-wide association study of type-2 diabetes (T2D) in individuals of South Asian ancestry. Our discovery set included 5,561 individuals with T2D (cases) and 14,458 controls drawn from studies in London, Pakistan and Singapore. We identified 20 independent SNPs associated with T2D at P < 10(-4) for testing in a replication sample of 13,170 cases and 25,398 controls, also all of South Asian ancestry. In the combined analysis, we identified common genetic variants at six loci (GRB14, ST6GAL1, VPS26A, HMG20A, AP3S2 and HNF4A) newly associated with T2D (P = 4.1 × 10(-8) to P = 1.9 × 10(-11)). SNPs at GRB14 were also associated with insulin sensitivity (P = 5.0 × 10(-4)), and SNPs at ST6GAL1 and HNF4A were also associated with pancreatic beta-cell function (P = 0.02 and P = 0.001, respectively). Our findings provide additional insight into mechanisms underlying T2D and show the potential for new discovery from genetic association studies in South Asians, a population with increased susceptibility to T2D.

In the past few years, new genetic risk factors for type 2 diabetes mellitus have been identified in large-scale studies of genetic associations. But can their inclusion in clinically based risk models improve disease prediction?

The mitochondria are the major cellular site of energy production and respiration. Recent research has focused on investigating the role of mitochondria in disease development and it has become increasingly evident that mitochondrial dysfunction contributes to a variety of human diseases. Mitochondrial DNA (mtDNA) quantity is very important for maintaining mitochondrial function and meeting the energy needs of the body. We have measured mitochondrial content in 1259 Mexican American individuals (from 42 extended families) and have shown that mtDNA quantity (a surrogate measure of mitochondrial integrity) has a large genetic component. We performed a genome scan and a genome-wide quantitative transcriptomic scan to identify QTLs influencing mitochondrial content. A variance components linkage-based genome scan utilizing 439 STR markers was used to localize a QTL for mitochondrial content on chromosome 10q (LOD = 3.83). Significant linkage to the mitochondrial genome was also detected for mitochondrial transmission (LOD = 3.39). For replication, we measured mitochondrial content in an independent Caucasian population (1088 individuals) finding evidence for linkage in these same regions. As part of the San Antonio Family Heart Study, we obtained genome-wide quantitative transcriptional profiles from 1240 individuals. Using lymphocyte samples, we quantitated 20 413 transcripts and examined correlations between the expression levels of these transcripts and mitochondrial content using the variance components method. Using regression analysis allowing for residual genetic components, we identified 829 transcripts (including many novel genes) influencing mitochondrial content that vary in their general biological actions, from cell signaling to cell trafficking and ion binding.

Pre-eclampsia/eclampsia (PE/E) is a common and serious disorder of human pregnancy that is associated with substantial maternal and perinatal morbidity and mortality. The suspected aetiology of PE/E is complex, with susceptibility being attributable to multiple environmental factors and a large genetic component. By assuming that the underlying liability towards PE/E susceptibility is inherently quantitative, any PE/E susceptibility gene would represent a quantitative trait locus (QTL). This assumption enables a more refined and powerful variance components procedure using a threshold model for our PE/E statistical analysis. Using this more efficient linkage approach, we have now re-analysed our previously completed Australian/New Zealand genome scan data to identify two novel PE/E susceptibility QTLs on chromosomes 5q and 13q. We have obtained strong evidence of linkage on 5q with a peak logarithm-of-odds (LOD) score of 3.12 between D5S644 and D5S433 [at approximately 121 centimorgan (cM)] and strong evidence of linkage on 13q with a peak LOD score of 3.10 between D13S1265 and D13S173 (at approximately 123 cM). Objective identification and prioritization of positional candidate genes using the quantitative bioinformatics program GeneSniffer revealed highly plausible PE/E candidate genes encoding aminopeptidase enzymes and a placental peptide hormone on the 5q QTL and two type IV collagens on the 13q QTL regions, respectively.