Replication Study in a Japanese Population of Six Susceptibility Loci for Type 2 Diabetes Originally Identified by a Transethnic Meta-Analysis of Genome-Wide Association Studies

<div><p>Aim</p><p>We performed a replication study in a Japanese population to evaluate the association between type 2 diabetes and six susceptibility loci (<i>TMEM154</i>, <i>SSR1</i>, <i>FAF1</i>, <i>POU5F1</i>, <i>ARL15</i>, and <i>MPHOSPH9</i>) originally identified by a transethnic meta-analysis of genome-wide association studies (GWAS) in 2014.</p><p>Methods</p><p>We genotyped 7,620 Japanese participants (5,817 type 2 diabetes patients and 1,803 controls) for each of the single nucleotide polymorphisms (SNPs) using a multiplex polymerase chain reaction invader assay. The association of each SNP locus with the disease was evaluated using logistic regression analysis.</p><p>Results</p><p>Of the six SNPs examined in this study, four (rs6813195 near <i>TMEM154</i>, rs17106184 in <i>FAF1</i>, rs3130501 in <i>POU5F1</i> and rs4275659 near <i>MPHOSPH9</i>) had the same direction of effect as in the original reports, but two (rs9505118 in <i>SSR1</i> and rs702634 in <i>ARL15</i>) had the opposite direction of effect. Among these loci, rs3130501 and rs4275659 were nominally associated with type 2 diabetes (rs3130501; p = 0.017, odds ratio [OR] = 1.113, 95% confidence interval [CI] 1.019–1.215, rs4275659; p = 0.012, OR = 1.127, 95% CI 1.026–1.238, adjusted for sex, age and body mass index), but we did not observe a significant association with type 2 diabetes for any of the six evaluated SNP loci in our Japanese population.</p><p>Conclusions</p><p>Our results indicate that effects of the six SNP loci identified in the transethnic GWAS meta-analysis are not major among the Japanese, although SNPs in <i>POU5F1</i> and <i>MPHOSPH9</i> loci may have some effect on susceptibility to type 2 diabetes in this population.</p></div

Replication Study for the Association of 9 East Asian GWAS-Derived Loci with Susceptibility to Type 2 Diabetes in a Japanese Population

<div><p>Aims</p><p>East Asian genome-wide association studies (GWAS) for type 2 diabetes identified 8 loci with genome-wide significance, and 2 loci with a borderline association. However, the associations of these loci except <i>MAEA</i> locus with type 2 diabetes have not been evaluated in independent East Asian cohorts. We performed a replication study to investigate the association of these susceptibility loci with type 2 diabetes in an independent Japanese population.</p> <p>Methods</p><p>We genotyped 7,379 Japanese participants (5,315 type 2 diabetes and 2,064 controls) for each of the 9 single nucleotide polymorphisms (SNPs), rs7041847 in <i>GLIS3</i>, rs6017317 in <i>FITM2</i>−<i>R3HDML</i>−<i>HNF4A</i>, rs6467136 near <i>GCCI</i>−<i>PAX4</i>, rs831571 near <i>PSMD6</i>, rs9470794 in <i>ZFAND3</i>, rs3786897 in <i>PEPD</i>, rs1535500 in <i>KCNK16</i>, rs16955379 in <i>CMIP</i>, and rs17797882 near <i>WWOX</i>. Because the sample size in this study was not sufficient to replicate single SNP associations, we constructed a genetic risk score (GRS) by summing a number of risk alleles of the 9 SNPs, and examined the association of the GRS with type 2 diabetes using logistic regression analysis.</p> <p>Results</p><p>With the exception of rs1535500 in <i>KCNK16</i>, all SNPs had the same direction of effect (odds ratio [OR]>1.0) as in the original reports. The GRS constructed from the 9 SNPs was significantly associated with type 2 diabetes in the Japanese population (<i>p</i> = 4.0 × 10^-4, OR = 1.05, 95% confidence interval: 1.02–1.09). In quantitative trait analyses, rs16955379 in <i>CMIP</i> was nominally associated with a decreased homeostasis model assessment of β-cell function and with increased fasting plasma glucose, but neither the individual SNPs nor the GRS showed a significant association with the glycemic traits.</p> <p>Conclusions</p><p>These results indicate that 9 loci that were identified in the East Asian GWAS meta-analysis have a significant effect on the susceptibility to type 2 diabetes in the Japanese population.</p> </div

A Single Nucleotide Polymorphism within <em>DUSP9</em> Is Associated with Susceptibility to Type 2 Diabetes in a Japanese Population

<div><h3>Aims</h3><p>The <em>DUSP9</em> locus on chromosome X was identified as a susceptibility locus for type 2 diabetes in a meta-analysis of European genome-wide association studies (GWAS), and GWAS in South Asian populations identified 6 additional single nucleotide polymorphism (SNP) loci for type 2 diabetes. However, the association of these loci with type 2 diabetes have not been examined in the Japanese. We performed a replication study to investigate the association of these 7 susceptibility loci with type 2 diabetes in the Japanese population.</p> <h3>Methods</h3><p>We genotyped 11,319 Japanese participants (8,318 with type 2 diabetes and 3,001 controls) for each of the 7 SNPs–rs5945326 near <em>DUSP9</em>, rs3923113 near <em>GRB14</em>, rs16861329 in <em>ST6GAL1</em>, rs1802295 in <em>VPS26A</em>, rs7178572 in <em>HMG20A</em>, rs2028299 near <em>AP3S2</em>, and rs4812829 in <em>HNF4A</em>–and examined the association of each of these 7 SNPs with type 2 diabetes by using logistic regression analysis.</p> <h3>Results</h3><p>All SNPs had the same direction of effect (odds ratio [OR]>1.0) as in the original reports. One SNP, rs5945326 near DUSP9, was significantly associated with type 2 diabetes at a genome-wide significance level (p = 2.21×10⁻⁸; OR 1.39, 95% confidence interval [CI]: 1.24−1.56). The 6 SNPs derived from South Asian GWAS were not significantly associated with type 2 diabetes in the Japanese population by themselves (<em>p</em>≥0.007). However, a genetic risk score constructed from 6 South Asian GWAS derived SNPs was significantly associated with Japanese type 2 diabetes (<em>p</em> = 8.69×10⁻⁴, OR  = 1.06. 95% CI; 1.03−1.10).</p> <h3>Conclusions/interpretation</h3><p>These results indicate that the <em>DUSP9</em> locus is a common susceptibility locus for type 2 diabetes across different ethnicities, and 6 loci identified in South Asian GWAS also have significant effect on susceptibility to Japanese type 2 diabetes.</p> </div

The Construction of Risk Prediction Models Using GWAS Data and Its Application to a Type 2 Diabetes Prospective Cohort

<div><p>Recent genome-wide association studies (GWAS) have identified several novel single nucleotide polymorphisms (SNPs) associated with type 2 diabetes (T2D). Various models using clinical and/or genetic risk factors have been developed for T2D risk prediction. However, analysis considering algorithms for genetic risk factor detection and regression methods for model construction in combination with interactions of risk factors has not been investigated. Here, using genotype data of 7,360 Japanese individuals, we investigated risk prediction models, considering the algorithms, regression methods and interactions. The best model identified was based on a Bayes factor approach and the lasso method. Using nine SNPs and clinical factors, this method achieved an area under a receiver operating characteristic curve (AUC) of 0.8057 on an independent test set. With the addition of a pair of interaction factors, the model was further improved (p-value 0.0011, AUC 0.8085). Application of our model to prospective cohort data showed significantly better outcome in disease-free survival, according to the log-rank trend test comparing Kaplan-Meier survival curves (). While the major contribution was from clinical factors rather than the genetic factors, consideration of genetic risk factors contributed to an observable, though small, increase in predictive ability. This is the first report to apply risk prediction models constructed from GWAS data to a T2D prospective cohort. Our study shows our model to be effective in prospective prediction and has the potential to contribute to practical clinical use in T2D.</p></div

Genotype distributions for 7 SNPs in case and control groups.

a<p>Males are coded as homozygous, and homozygous women and all men are included in the analysis.</p

Characteristics of participants.

a<p>Data are mean ± SD.</p>b<p>Chi-square test.</p>c<p>Student’s unpaired t-test.</p><p>BMI: body mass index, HbA1c: Glycated hemoglobin, PG: plasma glucose, TC: total cholesterol, TG: triglyceride, HDL-C: high density lipoprotein cholesterol, SBP: systolic blood pressure.</p

Association of 6 SNP loci with type 2 diabetes in a Japanese population.

<p>Association of 6 SNP loci with type 2 diabetes in a Japanese population.</p

A list of significant interaction factors.

<p>*gene associated with T2D.</p

Association of rs8090011 in <i>LAMA1</i> with quantitative traits related to glucose metabolism in obese controls (BMI ≥ 25) or in non-obese controls (BMI < 25).

<p>Results of linear regression analysis with adjustment for age, sex and BMI are presented.</p><p>^a Risk allele reported in the previous reports</p><p>^b values are log-transformed for the analysis</p><p>BMI < 25; n = 428 for HOMA-IR and HOMA-β, n = 482 for FPG</p><p>BMI ≥ 25; n = 374 for HOMA-IR and HOMA-β, n = 662 for FPG</p><p>Association of rs8090011 in <i>LAMA1</i> with quantitative traits related to glucose metabolism in obese controls (BMI ≥ 25) or in non-obese controls (BMI < 25).</p

The ROC curve for our risk prediction model.

<p>Sensitivity and specificity was maximized at a sensitivity of 0.858 and specificity of 0.623.</p