You will be presented with the abstract, introduction, and discussion section from a biomedical research article. Your task is to create a summary that a layperson can understand, capturing the essence of the research article. Keep essential scientific terms, but ensure that the language remains clear and the concepts are explained in an uncomplicated manner.

Title: Transferability of Type 2 Diabetes Implicated Loci in Multi-Ethnic
                    Cohorts from Southeast Asia}
Article:
Abstract:
Recent large genome-wide association studies( GWAS) have identified multiple loci which harbor genetic variants associated with type 2 diabetes mellitus( T2D), many of which encode proteins not previously suspected to be involved in the pathogenesis of T2D. Most GWAS for T2D have focused on populations of European descent, and GWAS conducted in other populations with different ancestry offer a unique opportunity to study the genetic architecture of T2D. We performed genome-wide association scans for T2D in 3, 955 Chinese( 2, 010 cases, 1, 945 controls), 2, 034 Malays( 794 cases, 1, 240 controls), and 2, 146 Asian Indians( 977 cases, 1, 169 controls). In addition to the search for novel variants implicated in T2D, these multi-ethnic cohorts serve to assess the transferability and relevance of the previous findings from European descent populations in the three major ethnic populations of Asia, comprising half of the world's population. Of the SNPs associated with T2D in previous GWAS, only variants at CDKAL1 and HHEX/IDE/KIF11 showed the strongest association with T2D in the meta-analysis including all three ethnic groups. However, consistent direction of effect was observed for many of the other SNPs in our study and in those carried out in European populations. Close examination of the associations at both the CDKAL1 and HHEX/IDE/KIF11 loci provided some evidence of locus and allelic heterogeneity in relation to the associations with T2D. We also detected variation in linkage disequilibrium between populations for most of these loci that have been previously identified. These factors, combined with limited statistical power, may contribute to the failure to detect associations across populations of diverse ethnicity. These findings highlight the value of surveying across diverse racial/ethnic groups towards the fine-mapping efforts for the casual variants and also of the search for variants, which may be population-specific.
Introduction:
Type 2 diabetes mellitus( T2D) is a major chronic disease worldwide, affecting more than 300 million people. The greatest increase in the prevalence of T2D in the coming years is likely to be in Asia, home to half of the world's population with 3 billion people[1]–[2]. It is estimated that in China alone, there are 100 million people with T2D[3]. T2D has been one of the major human diseases to benefit from the advent of large-scale genetic studies that survey the entire genomic landscape for variants correlating with disease onset or severity. These genome-wide association studies( GWAS) have identified a number of novel loci harboring common variants that are associated with an increased risk of T2D[4]–[11], adding to the loci previously identified by candidate gene studies( PPARG[12], KCNJ11[13]–[14], WFS1[15]–[16]) and linkage studies TCF7L2[17]–[19]). There have been fewer GWAS of T2D performed in non-European populations, namely in the Japanese[20], Han Chinese in Taiwan[21] and South Asians in the United Kingdom[22]. These latter studies, however, are important for the following reasons:( i) the frequencies of genuinely implicated variants may differ across ethnic groups, and these studies may discover novel regions that have been overlooked in previous studies due to lower risk allele frequencies in populations of European ancestry;( ii) ethnicity may modulate the associations between common variants and T2D, such that the same locus may exert different effects in other populations due to differences in genetic background or environmental exposures;( iii) the pathogenesis of T2D may be heterogeneous across populations, resulting in differing importance of genetic susceptibility to a particular loci. Examples of novel findings emerging from the Asian GWAS include variants in KCNQ1[8]–[9], PTPRD[21], SRR[21] and PEPD[20]. Of these, only the association at KCNQ1 has been extensively replicated[11],[20]–[21],[23]–[30]. The discovery of these genetic loci for T2D is exciting, since it heralds the prospect of identifying novel therapeutic targets for its treatment and prevention. For example, PPARG and KCNJ11 both harbor common genetic variants associated with T2D and are both therapeutic targets for drugs used to lower blood glucose[12]–[13]. However, at present, there is limited information on the relevance of the identified loci across multiple populations, as these discoveries have primarily been made in populations of European ancestry. Even if the same locus is causally implicated with T2D onset in multiple populations, it is unclear whether the genetic effect estimated from these studies is representative in other non-European populations. One common strategy of evaluating the transferability and the genetic effects of the associated loci is to replicate the index SNPs that have been identified by the genome-wide surveys. Many of these studies, conducted in individuals of Han Chinese, Japanese, Asian Indians, exhibited replication for many of the index SNPs that emerged from the first wave of T2D GWAS[4]–[7] with consistent direction of effect[20],[23]–[24],[30]–[45]. However, replication efforts for the more recently identified SNPs have been less successful[32],[46]–[48]. Failure to replicate the original associations at the index SNPs in heterogeneous populations does not necessarily indicate that these loci are not involved in T2D pathogenesis in these populations. As these SNPs are unlikely to be the biologically functional polymorphisms but merely in linkage disequilibrium( LD) with the underlying causal variants, the index SNPs identified from European populations may be poorly correlated with the causal variants in other populations such that studies aiming to reproduce only the original associations are under-powered and thus are unable to observe any statistical evidence at these SNPs. GWAS carried out in non-European populations can also address the two issues of transferability and consistency of the genetic etiology between populations with differing ancestry. The multi-ethnic demography of Singapore, consisting mainly of Chinese, Malays and Asian Indians, possesses vast potential for investigating the genetic etiology of T2D. Importantly, these populations broadly capture the genetic diversity across Asia, home to almost three billion people, and especially in a large proportion of the populations that are likely to experience the greatest increase in the burden of T2D in the near future[1]. Here we describe three separate genome-wide surveys of T2D in the Chinese, Malay and Asian Indian populations assaying a total of 10, 718 individuals, yielding a post-QC sample size of 3, 781 cases and 4, 354 controls. With this resource, we set out:( i) to identify any novel genetic variants that are associated with T2D in these ethnic groups;( ii) to examine the genetic architecture of the previously established T2D loci in the heterogeneous settings offered by the three ethnic groups; and( iii) to estimate the magnitude of the effects at variants that replicate in our populations.
Discussion:
We have performed three genome-wide case-control surveys of T2D in Chinese, Malays and Asian Indians in Singapore. To the best of our knowledge, this is the first GWAS to be performed in Malays, which forms the largest population group in Southeast Asia, comprising more than 300 million people. A meta-analysis of these three studies showed strong associations at the CDKAL1 and HHEX/IDE/KIF11 loci that have consistently emerged in T2D studies in multiple global populations. More importantly, the availability of genome-wide data across these three major population groups allowed us to evaluate the transferability and relevance of the previously established genomic regions that are involved in the pathogenesis of T2D. In addition, we investigated the genetic architecture at CDKAL1 and HHEX/IDE/KIF11, showing evidence of population-specific effects, allelic heterogeneity and LD variations at these loci across our three populations. Of note, our study failed to detect statistically significant associations for a number of the variants that had been discovered and validated in previous studies, mostly in European populations. One potential reason relates to the power of our studies to detect these associations. Several things contribute to the limited power in our studies. Firstly, the sample sizes in our individual studies were relatively small, especially compared to the European consortia. Secondly, at several of these loci, the allele frequencies were lower in our studies than in European populations. The impact of low allele frequencies is exemplified for variants at the TCF7L2 locus, which exhibited the greatest effects on T2D risk in European populations. The frequencies of the risk allele at TCF7L2( rs7903146) were 0. 023 in the Chinese and 0. 043 in the Malays, compared to 0. 285 in the Indians( which is similar to that observed in European populations). While the direction and magnitude of the effects sizes were similar in our populations and previous reports[24],[49]–[50], statistical significance was only observed in the Indian GWAS. This impact of low allele frequency is consistent with the finding in a Japanese population that found associations with TCF7L2 variants with T2D in the same direction in European populations, when the sample size was sufficiently large[20]. Based on the allele frequencies observed in our studies and the sample sizes available, we had at least 80% power to detect the associations for only 8( TCF7L2, HNF1B, UBE2E2, CDKAL1, SLC30A8, HHEX, KCNQ1 and SRR) of the 36 variants in the Chinese( the ethnic group with the largest sample size), 1 in the Malays( SRR) and 2 in the Indians( TCF7L2 and SRR). A third reason for the lack of power in our studies is that the effect sizes in our study were generally smaller than those observed in the initial studies that identified these variants. It is possible that the effect estimates of the initial discoveries were over-estimates( winner's curse). Other potential reasons for this include allelic heterogeneity or LD variation between populations which are discussed in the following paragraphs. For several of the variants where we had at least 80% power to detect an association at α = 0. 05, the effect sizes seen in our studies were smaller than those reported in the initial European populations. These include variants at the TCF7L2, SLC30A8 and KCNQ1 loci. It is noteworthy that the variants for which we were able to detect an association in our study were mostly discovered in the earlier wave of genome-wide scans for T2D( including CDKAL1, HHEX/IDE/KIF11, IGFBP2, SLC30A8 and FTO)[5]–[7],[51]. These early studies had smaller sample sizes and thus, variants identified generally had larger OR than those that emerged when large number of individuals were analyzed jointly( as is typical of meta-analyses of populations with European ancestry). Despite the limited power of our study to detect statistically significant associations, our study showed that, of the variants identified in European GWAS for T2D, there were more statistically significant associations detected in our study than could be expected by chance, and that the direction of association was consistent in our study and in studies conducted in European populations. This suggests that for many of the variants identified in European populations, the findings are likely to be relevant in Asian populations. The second reason for the failure to detect these associations may be due to the presence of allelic heterogeneity, where different and/or multiple causal variants may be responsible for the association signals observed at a locus in different populations. There is suggestive evidence from our study that CDKAL1 may harbour at least two separate functional polymorphisms in the Indians where adjustment for the lead SNP attenuated a set of signals but boosted the evidence in an upstream intronic region. Similarly, at the HHEX/IDE/KIF11 locus, there is evidence to suggest that the associations seen in Chinese( and to a certain extent, in Malays) originate from at least two separate functional polymorphisms, where the lead SNPs from our study( rs6583826) and from European studies( rs1111875) do not entirely account for the association signals observed at this locus. This finding is consistent with evidence that recently emerged from a large meta-analysis in populations of European ancestry that also identified more than 1 independent signal at several loci that were associated with T2D[11]. Finally, even when the same causal variant at a locus is present in different populations, heterogeneous patterns of LD between the causal variant and the genotyped SNPs may result in different variants emerging from GWAS in these populations. This can critically confound meta-analyses, which fundamentally assume that the same index SNP is implicated across multiple populations. Our analyses using varLD show that, for most T2D associated loci, significant LD variation exists between all pairs of ethnic groups, except Chinese and Malays. Unfortunately, despite this evidence of LD variation, our power calculations suggest that our studies are not adequately powered to detect these associations in the individual ethnic groups. As such, we are not able to examine heterogeneity between ethnic groups for most of these loci( apart from CDKAL1 and HHEX/IDE/KIF11). In such settings, statistical methods for assessing regional evidence across multiple studies without relying on observing phenotype associations at the same index SNP may be increasingly relevant and important. One important caveat of our study is the age profile of our control samples, which are generally younger than the cases, especially in the Chinese cohort. As some of the control individuals may subsequently develop T2D, the use of young controls likely has the effect of reducing statistical power and under-estimating the effect sizes. However, the signals of association at CDKAL1 are useful for calibrating the extent of this, and the effect sizes in our Chinese and Indian populations were similar or even larger than those reported in European studies despite comparable frequencies of the implicated alleles. The advent of GWAS allows an unbiased survey to be made across the entire human genome for novel genetic loci that are causally responsible for T2D onset. Presently, it is difficult to assess the implications of these genetic discoveries to global public health, primarily because these findings are typically identifying surrogate markers that likely do not have any bearing on genetic etiology of T2D. Fine-mapping the polymorphisms that are biologically responsible will present a significant advancement in addressing the relevance of any genetic discoveries in other populations. However, genetic and/or environmental modifiers resulting in population-specific effects and allelic heterogeneity can continue to confound the situation, even when the causal variants have been identified. This may have implications for subsequent studies that attempt to uncover the genetic architecture of T2D. It highlights the importance of conducting genetic surveys in T2D across multiple populations, particularly those that are likely to experience the greatest increase in T2D burden. This is even more pertinent as interest in medical genetics gradually shifts towards searching for rare variants, which are exactly those that are even more likely to be exclusive to specific populations.
Type 2 diabetes mellitus ( T2D ) is a chronic disease which can lead to complications such as heart disease , stroke , hypertension , blindness due to diabetic retinopathy , amputations from peripheral vascular diseases , and kidney disease from diabetic nephropathy . The increasing prevalence and complications of T2D are likely to increase the health and economic burden of individuals , families , health systems , and countries . Our study carried out in three major Asian ethnic groups ( Chinese , Malays , and Indians ) in Singapore suggests that the findings of studies carried out in populations of European ancestry ( which represents most studies to date ) may be relevant to populations in Asia . However , our study also raises the possibility that different genes , and within the genes different variants , may confer susceptibility to T2D in these populations . These findings are particularly relevant in Asia , where the greatest growth of T2D is expected in the coming years , and emphasize the importance of studying diverse populations when trying to localize the regions of the genome associated with T2D . In addition , we may need to consider novel methods for combining data across populations .