Meta-analysis of genome-wide association studies identifies common variants associated with blood pressure variation in east Asians

Kato, Norihiro,Takeuchi, Fumihiko,Tabara, Yasuharu,Kelly, Tanika N,Go, Min Jin,Sim, Xueling,Tay, Wan Ting,Chen, Chien-Hsiun,Zhang, Yi,Yamamoto, Ken,Katsuya, Tomohiro,Yokota, Mitsuhiro,Kim, Young Jin,O Nature Publishing Group, a division of Macmillan P 2011 Nature genetics Vol.43 No.6

We conducted a meta-analysis of genome-wide association studies of systolic (SBP) and diastolic (DBP) blood pressure in 19,608 subjects of east Asian ancestry from the AGEN-BP consortium followed up with de novo genotyping (n = 10,518) and further replication (n = 20,247) in east Asian samples. We identified genome-wide significant (P < 5 ? 10<SUP>??8</SUP>) associations with SBP or DBP, which included variants at four new loci (ST7L-CAPZA1, FIGN-GRB14, ENPEP and NPR3) and a newly discovered variant near TBX3. Among the five newly discovered variants, we obtained significant replication in the independent samples for all of these loci except NPR3. We also confirmed seven loci previously identified in populations of European descent. Moreover, at 12q24.13 near ALDH2, we observed strong association signals (P = 7.9 ? 10<SUP>??31</SUP> and P = 1.3 ? 10<SUP>??35</SUP> for SBP and DBP, respectively) with ethnic specificity. These findings provide new insights into blood pressure regulation and potential targets for intervention.

A meta-analysis of genome-wide association studies for adiponectin levels in East Asians identifies a novel locus near <i>WDR11-FGFR2</i>

Wu, Ying,Gao, He,Li, Huaixing,Tabara, Yasuharu,Nakatochi, Masahiro,Chiu, Yen-Feng,Park, Eun Jung,Wen, Wanqing,Adair, Linda S.,Borja, Judith B.,Cai, Qiuyin,Chang, Yi-Cheng,Chen, Peng,Croteau-Chonka, Da Oxford University Press 2014 Human Molecular Genetics Vol.23 No.4

<P>Blood levels of adiponectin, an adipocyte-secreted protein correlated with metabolic and cardiovascular risks, are highly heritable. Genome-wide association (GWA) studies for adiponectin levels have identified 14 loci harboring variants associated with blood levels of adiponectin. To identify novel adiponectin-associated loci, particularly those of importance in East Asians, we conducted a meta-analysis of GWA studies for adiponectin in 7827 individuals, followed by two stages of replications in 4298 and 5954 additional individuals. We identified a novel adiponectin-associated locus on chromosome 10 near <I>WDR11-FGFR2</I> (<I>P</I> = 3.0 × 10<SUP>−14</SUP>) and provided suggestive evidence for a locus on chromosome 12 near <I>OR8S1-LALBA</I> (<I>P</I> = 1.2 × 10<SUP>−7</SUP>). Of the adiponectin-associated loci previously described, we confirmed the association at <I>CDH13</I> (<I>P</I> = 6.8 × 10<SUP>−165</SUP>), <I>ADIPOQ</I> (<I>P</I> = 1.8 × 10<SUP>−22</SUP>), <I>PEPD</I> (<I>P</I> = 3.6 × 10<SUP>−12</SUP>), <I>CMIP</I> (<I>P</I> = 2.1 × 10<SUP>−10</SUP>), <I>ZNF664</I> (<I>P</I> = 2.3 × 10<SUP>−7</SUP>) and <I>GPR109A</I> (<I>P</I> = 7.4 × 10<SUP>−6</SUP>). Conditional analysis at <I>ADIPOQ</I> revealed a second signal with suggestive evidence of association only after conditioning on the lead SNP (<I>P</I><SUB>initial</SUB> = 0.020; <I>P</I><SUB>conditional</SUB> = 7.0 × 10<SUP>−7</SUP>). We further confirmed the independence of two pairs of closely located loci (<2 Mb) on chromosome 16 at <I>CMIP</I> and <I>CDH13</I>, and on chromosome 12 at <I>GPR109A</I> and <I>ZNF664</I>. In addition, the newly identified signal near <I>WDR11-FGFR2</I> exhibited evidence of association with triglycerides (<I>P</I> = 3.3 × 10<SUP>−4</SUP>), high density lipoprotein cholesterol (HDL-C, <I>P</I> = 4.9 × 10<SUP>−4</SUP>) and body mass index (BMI)-adjusted waist–hip ratio (<I>P</I> = 9.8 × 10<SUP>−3</SUP>). These findings improve our knowledge of the genetic basis of adiponectin variation, demonstrate the shared allelic architecture for adiponectin with lipids and central obesity and motivate further studies of underlying mechanisms.</P>

Genome-Wide Association Study Meta-Analysis Reveals Transethnic Replication of Mean Arterial and Pulse Pressure Loci

Kelly, Tanika N.,Takeuchi, Fumihiko,Tabara, Yasuharu,Edwards, Todd L.,Kim, Young Jin,Chen, Peng,Li, Huaixing,Wu, Ying,Yang, Chi-Fan,Zhang, Yonghong,Gu, Dongfeng,Katsuya, Tomohiro,Ohkubo, Takayoshi,Gao American Heart Association, Inc. 2013 Hypertension Vol.62 No.5

<P>We conducted a genome-wide association study meta-analysis of mean arterial pressure and pulse pressure among 26 600 East Asian participants (stage 1) followed by replication study of up to 28 783 participants (stage 2). For novel loci, statistical significance was determined by a <I>P</I><5.0×10<SUP>–8</SUP> in joint analysis of stage 1 and stage 2 data. For loci reported by the previous mean arterial and pulse pressure genome-wide association study meta-analysis in Europeans, evidence of transethnic replication was determined by consistency in effect direction and a Bonferroni-corrected <I>P</I><1.4×10<SUP>–3</SUP>. No novel loci were identified by the current study. Five independent mean arterial pressure variants demonstrated robust evidence for transethnic replication including rs17249754 at <I>ATP2B1</I> (<I>P</I>=7.5×10<SUP>–15</SUP>), rs2681492 at <I>ATP2B1</I> (<I>P</I>=3.4×10<SUP>–7</SUP>), rs11191593 at <I>NT5C2</I> (1.1×10<SUP>–6</SUP>), rs3824755 at <I>CYP17A1</I> (<I>P</I>=1.2×10<SUP>–6</SUP>), and rs13149993 at <I>FGF5</I> (<I>P</I>=2.4×10<SUP>–4</SUP>). Two additional variants showed suggestive evidence of transethnic replication (consistency in effect direction and <I>P</I><0.05), including rs319690 at <I>MAP4</I> (<I>P</I>=0.014) and rs1173771 at <I>NPR3</I> (<I>P</I>=0.018). For pulse pressure, robust evidence of replication was identified for 2 independent variants, including rs17249754 at <I>ATP2B1</I> (<I>P</I>=1.2×10<SUP>–5</SUP>) and rs11191593 at <I>NT5C2</I> (<I>P</I>=1.1×10<SUP>–3</SUP>), with suggestive evidence of replication among an additional 2 variants including rs3824755 at <I>CYP17A1</I> (<I>P</I>=6.1×10<SUP>–3</SUP>) and rs2681492 at <I>ATP2B1</I> (<I>P</I>=9.0×10<SUP>–3</SUP>). Replicated variants demonstrated consistency in effect sizes between East Asian and European samples, with effect size differences ranging from 0.03 to 0.24 mm Hg for mean arterial pressure and from 0.03 to 0.21 mm Hg for pulse pressure. In conclusion, we present the first evidence of transethnic replication of several mean arterial and pulse pressure loci in an East Asian population.</P>

Meta-analysis of genome-wide association studies in East Asian-ancestry populations identifies four new loci for body mass index

Wen, Wanqing,Zheng, Wei,Okada, Yukinori,Takeuchi, Fumihiko,Tabara, Yasuharu,Hwang, Joo-Yeon,Dorajoo, Rajkumar,Li, Huaixing,Tsai, Fuu-Jen,Yang, Xiaobo,He, Jiang,Wu, Ying,He, Meian,Zhang, Yi,Liang, Jun IRL Press 2014 Human molecular genetics Vol.23 No.20

<P>Recent genetic association studies have identified 55 genetic loci associated with obesity or body mass index (BMI). The vast majority, 51 loci, however, were identified in European-ancestry populations. We conducted a meta-analysis of associations between BMI and ∼2.5 million genotyped or imputed single nucleotide polymorphisms among 86 757 individuals of Asian ancestry, followed by <I>in silico</I> and <I>de novo</I> replication among 7488–47 352 additional Asian-ancestry individuals. We identified four novel BMI-associated loci near the <I>KCNQ1</I> (rs2237892, <I>P</I> = 9.29 × 10<SUP>−13</SUP>), <I>ALDH2/MYL2</I> (rs671, <I>P</I> = 3.40 × 10<SUP>−11</SUP>; rs12229654, <I>P</I> = 4.56 × 10<SUP>−9</SUP>), <I>ITIH4</I> (rs2535633, <I>P</I> = 1.77 × 10<SUP>−10</SUP>) and <I>NT5C2</I> (rs11191580, <I>P</I> = 3.83 × 10<SUP>−8</SUP>) genes. The association of BMI with rs2237892, rs671 and rs12229654 was significantly stronger among men than among women. Of the 51 BMI-associated loci initially identified in European-ancestry populations, we confirmed eight loci at the genome-wide significance level (<I>P</I> < 5.0 × 10<SUP>−8</SUP>) and an additional 14 at <I>P</I> < 1.0 × 10<SUP>−3</SUP> with the same direction of effect as reported previously. Findings from this analysis expand our knowledge of the genetic basis of obesity.</P>

A Common Variant in SLC8A1 Is Associated with the Duration of the Electrocardiographic QT Interval

Kim, J.,Hong, K.W.,Go, M.,Kim, S.,Tabara, Y.,Kita, Y.,Tanigawa, T.,Cho, Y.,Han, B.G.,Oh, B. University of Chicago Press [etc.] 2012 American journal of human genetics Vol.91 No.1

Prolongation of the electrocardiographic QT interval, a measure of cardiac repolarization, predisposes one to ventricular arrhythmias and sudden cardiac death. Since NOS1AP, a regulator of neuronal nitric oxide synthase, was discovered in a genome-wide association study (GWAS) as a novel target that modulates cardiac repolarization, several loci have been linked to the QT interval in studies (QTGEN and QTSCD) of European descendents. However, there has been no GWAS of the QT interval in Asian populations. We conducted a GWAS with regard to the QT interval in Korea Association Resource (KARE [n = 6,805]) cohorts. Replication studies in independent populations of Korean (n = 4,686) and Japanese (n = 2,687) groups validated the association between a SNP, rs13017846, which maps to near SLC8A1 (sodium/calcium exchanger 1 precursor, overall p = 8.0 x 10<SUP>-14</SUP>), and the QT interval. The minor allele frequency (MAF) of rs13017846 varies widely between ethnicities-0.053 in Europeans (HapMap CEU [Utah residents with ancestry from northern and western Europe from the Centre d'Etude du Polymorphisme Humain collection] samples) versus 0.080 in Africans (HapMap YRI [Yoruba in Ibadan, Nigeria] samples)-whereas a MAF of 0.500 has been reported in Asians (HapMap HCB [Han Chinese in Beijing, China] and JPT [Japanese in Tokyo, Japan] samples). This might explain why this locus has not been identified in Europeans in previous studies.

Identification of three novel genetic variations associated with electrocardiographic traits (QRS duration and PR interval) in East Asians

Hong, Kyung-Won,Lim, Ji Eun,Kim, Jong Wook,Tabara, Yasuharu,Ueshima, Hirotsugu,Miki, Tetsuro,Matsuda, Fumihiko,Cho, Yoon Shin,Kim, Yeonjung,Oh, Bermseok IRL Press 2014 Human molecular genetics Vol.23 No.24

<P>The electrocardiogram has several advantages in detecting cardiac arrhythmia—it is readily available, noninvasive and cost-efficient. Recent genome-wide association studies have identified single-nucleotide polymorphisms that are associated with electrocardiogram measures. We performed a genome-wide association study using Korea Association Resource data for the discovery phase (Phase 1, <I>n</I> = 6805) and two consecutive replication studies in Japanese populations (Phase 2, <I>n</I> = 2285; Phase 3, <I>n</I> = 5010) for QRS duration and PR interval. Three novel loci were identified: rs2483280 (<I>PRDM16</I> locus) and rs335206 (<I>PRDM6</I> locus) were associated with QRS duration, and rs17026156 (<I>SLC8A1</I> locus) correlated with PR interval. <I>PRDM16</I> was recently identified as a causative gene of left ventricular non-compaction and dilated cardiomyopathy in 1p36 deletion syndrome, which is characterized by heart failure, arrhythmia and sudden cardiac death. Thus, our finding that a <I>PRDM16</I> SNP is linked to QRS duration strongly implicates <I>PRDM16</I> in cardiac function. In addition, C allele of rs17026156 increases PR interval (beta ± SE, 2.39 ± 0.40 ms) and exists far more frequently in East Asians (0.46) than in Europeans and Africans (0.05 and 0.08, respectively).</P>