Large-scale genome-wide association study of Asian population reveals genetic factors in FRMD4A and other loci influencing smoking initiation and nicotine dependence.

Yoon, Dankyu,Kim, Young-Jin,Cui, Wen-Yan,Van der Vaart, Andrew,Cho, Yoon Shin,Lee, Jong-Young,Ma, Jennie Z,Payne, Thomas J,Li, Ming D,Park, Taesung Springer-Verlag 2012 HUMAN GENETICS Vol.131 No.6

<P>Diseases related to smoking are the second leading cause of death in the world. Cigarette smoking is a risk factor for several diseases such as cancer and cardiovascular and respiratory disorders. Despite increasing evidence of genetic determination, the susceptibility genes and loci underlying various aspects of smoking behavior are largely unknown. Moreover, almost all reported genome-wide association studies (GWASs) have been performed on samples of European origin, limiting the applicability of the results to other ethnic populations. In this first GWAS on smoking behavior in an Asian population, after analyzing 8,842 DNA samples from the Korea Association Resource project with 352,228 single nucleotide polymorphisms (SNPs) genotyped for each sample, we identified 8 SNPs significantly associated with smoking initiation (SI) and 4 with nicotine dependence (ND). Because of the current unavailability of an independent Asian smoking sample, we replicated the discoveries in independent samples of European-American and African-American origin. Of the 12 SNPs examined in the replicated samples, we identified two SNPs, in the regulator of G-protein signaling 17 gene (rs7747583, p value(meta)?=?6.40??10(-6); rs2349433, p value(meta)?=?5.57??10(-6)), associated with SI. Also, we found two SNPs significantly associated with ND; one in the FERM domain containing 4A (rs4424567, p value(meta)?=?2.30??10(-6)) and the other at 7q31.1 (rs848353, p value(meta)?=?9.16??10(-8)). These SNPs represent novel targets for examination of smoking behavior and warrant further investigation using independent samples.</P>

Robust imputation method for missing values in microarray data

Yoon, Dankyu,Lee, Eun-Kyung,Park, Taesung BioMed Central 2007 BMC bioinformatics Vol.8 No.suppl2

<P><B>Background</B></P><P>When analyzing microarray gene expression data, missing values are often encountered. Most multivariate statistical methods proposed for microarray data analysis cannot be applied when the data have missing values. Numerous imputation algorithms have been proposed to estimate the missing values. In this study, we develop a robust least squares estimation with principal components (RLSP) method by extending the local least square imputation (LLSimpute) method. The basic idea of our method is to employ quantile regression to estimate the missing values, using the estimated principal components of a selected set of similar genes.</P><P><B>Results</B></P><P>Using the normalized root mean squares error, the performance of the proposed method was evaluated and compared with other previously proposed imputation methods. The proposed RLSP method clearly outperformed the weighted <I>k</I>-nearest neighbors imputation (kNNimpute) method and LLSimpute method, and showed competitive results with Bayesian principal component analysis (BPCA) method.</P><P><B>Conclusion</B></P><P>Adapting the principal components of the selected genes and employing the quantile regression model improved the robustness and accuracy of missing value imputation. Thus, the proposed RLSP method is, according to our empirical studies, more robust and accurate than the widely used kNNimpute and LLSimpute methods.</P>

A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits

Cho, Yoon Shin,Go, Min Jin,Kim, Young Jin,Heo, Jee Yeon,Oh, Ji Hee,Ban, Hyo-Jeong,Yoon, Dankyu,Lee, Mi Hee,Kim, Dong-Joon,Park, Miey,Cha, Seung-Hun,Kim, Jun-Woo,Han, Bok-Ghee,Min, Haesook,Ahn, Younjhi Nature Publishing Group 2009 Nature genetics Vol.41 No.5

To identify genetic factors influencing quantitative traits of biomedical importance, we conducted a genome-wide association study in 8,842 samples from population-based cohorts recruited in Korea. For height and body mass index, most variants detected overlapped those reported in European samples. For the other traits examined, replication of promising GWAS signals in 7,861 independent Korean samples identified six previously unknown loci. For pulse rate, signals reaching genome-wide significance mapped to chromosomes 1q32 (rs12731740, P = 2.9 × 10<SUP>−9</SUP>) and 6q22 (rs12110693, P = 1.6 × 10<SUP>−9</SUP>), with the latter ∼400 kb from the coding sequence of GJA1. For systolic blood pressure, the most compelling association involved chromosome 12q21 and variants near the ATP2B1 gene (rs17249754, P = 1.3 × 10<SUP>−7</SUP>). For waist-hip ratio, variants on chromosome 12q24 (rs2074356, P = 7.8 × 10<SUP>−12</SUP>) showed convincing associations, although no regional transcript has strong biological candidacy. Finally, we identified two loci influencing bone mineral density at multiple sites. On chromosome 7q31, rs7776725 (within the FAM3C gene) was associated with bone density at the radius (P = 1.0 × 10<SUP>−11</SUP>), tibia (P = 1.6 × 10<SUP>−6</SUP>) and heel (P = 1.9 × 10<SUP>−10</SUP>). On chromosome 7p14, rs1721400 (mapping close to SFRP4, a frizzled protein gene) showed consistent associations at the same three sites (P = 2.2 × 10<SUP>−3</SUP>, P = 1.4 × 10<SUP>−7</SUP> and P = 6.0 × 10<SUP>−4</SUP>, respectively). This large-scale GWA analysis of well-characterized Korean population-based samples highlights previously unknown biological pathways.

Age-Related Changes in Immunological Factors and Their Relevance in Allergic Disease Development During Childhood

장우성,김은진,임연미,Dankyu Yoon,손주영,박중원,홍수종,조상헌,이주실 대한천식알레르기학회 2016 Allergy, Asthma & Immunology Research Vol.8 No.4

Purpose: Allergic diseases are triggered by Th2-mediated immune reactions to allergens and orchestrated by various immunological factors, including immune cells and cytokines. Although many reports have suggested that childhood is the critical period in the onset of allergic diseases and aging leads to alter the susceptibility of an individual to allergic diseases, age-related changes in various immunological factors in healthy individuals as well as their difference between healthy and allergic children have not yet been established. Methods: We investigated the ratio of Th1/Th2 cells and the levels of 22 allergy-related cytokines across all age groups in individuals who were classified as clinically non-atopic and healthy. We also examined their differences between healthy and allergic children to evaluate immunological changes induced by the development of allergic diseases during childhood. Results: The Th1/Th2 ratio rose gradually during the growth period including childhood, reaching peak values in the twenties-thirties age group. Th1/Th2 ratios were significantly lower in allergic children than in healthy controls, whereas 14 of 22 cytokines were significantly higher in allergic children than in healthy controls. On the other hand, there were no differences in Th1/Th2 ratios and cytokines between healthy and allergic adolescents. Conclusions: In this study, age-related changes in Th1/Th2 ratios were found in normal controls across all age groups, and decreases in Th1/Th2 ratio were observed with increasing of 14 cytokines in allergic children. The results of this study may be helpful as reference values for both monitoring immunological changes according to aging in healthy individuals and distinguishing between normal and allergic subjects in terms of immune cells and soluble factors.

Role of an unclassified Lachnospiraceae in the pathogenesis of type 2 diabetes: a longitudinal study of the urine microbiome and metabolites

Kim Kangjin,Lee Sanghun,Park Sang-Chul,Kim Nam-Eun,Shin Chol,Lee Seung Ku,Jung Youngae,Yoon Dankyu,Kim Hyeonjeong,Kim Sanghyun,Hwang Geum-Sook,Won Sungho 생화학분자생물학회 2022 Experimental and molecular medicine Vol.54 No.-

Recent investigations have revealed that the human microbiome plays an essential role in the occurrence of type 2 diabetes (T2D). However, despite the importance of understanding the involvement of the microbiota throughout the body in T2D, most studies have focused specifically on the intestinal microbiota. Extracellular vesicles (EVs) have been recently found to provide important evidence regarding the mechanisms of T2D pathogenesis, as they act as key messengers between intestinal microorganisms and the host. Herein, we explored microorganisms potentially associated with T2D by tracking changes in microbiota-derived EVs from patient urine samples collected three times over four years. Mendelian randomization analysis was conducted to evaluate the causal relationships among microbial organisms, metabolites, and clinical measurements to provide a comprehensive view of how microbiota can influence T2D. We also analyzed EV-derived metagenomic (N = 393), clinical (N = 5032), genomic (N = 8842), and metabolite (N = 574) data from a prospective longitudinal Korean community-based cohort. Our data revealed that GU174097_g, an unclassified Lachnospiraceae, was associated with T2D (β = −189.13; p = 0.00006), and it was associated with the ketone bodies acetoacetate and 3-hydroxybutyrate (r = −0.0938 and −0.0829, respectively; p = 0.0022 and 0.0069, respectively). Furthermore, a causal relationship was identified between acetoacetate and HbA1c levels (β = 0.0002; p = 0.0154). GU174097_g reduced ketone body levels, thus decreasing HbA1c levels and the risk of T2D. Taken together, our findings indicate that GU174097_g may lower the risk of T2D by reducing ketone body levels.

A genome-wide association study of a coronary artery disease risk variant.

Lee, Ji-Young,Lee, Bok-Soo,Shin, Dong-Jik,Woo Park, Kyung,Shin, Young-Ah,Joong Kim, Kwang,Heo, Lyong,Young Lee, Ji,Kyoung Kim, Yun,Jin Kim, Young,Bum Hong, Chang,Lee, Sang-Hak,Yoon, Dankyu,Jung Ku, Hy Springer-Verlag 2013 Journal of human genetics Vol.58 No.3

<P>Although over 30 common genetic susceptibility loci have been identified to be independently associated with coronary artery disease (CAD) risk through genome-wide association studies (GWAS), genetic risk variants reported to date explain only a small fraction of heritability. To identify novel susceptibility variants for CAD and confirm those previously identified in European population, GWAS and a replication study were performed in the Koreans and Japanese. In the discovery stage, we genotyped 2123 cases and 3591 controls with 521 786 SNPs using the Affymetrix SNP Array 6.0 chips in Korean. In the replication, direct genotyping was performed using 3052 cases and 4976 controls from the KItaNagoya Genome study of Japan with 14 selected SNPs. To maximize the coverage of the genome, imputation was performed based on 1000 Genome JPT+CHB and 5.1 million SNPs were retained. CAD association was replicated for three GWAS-identified loci (1p13.3/SORT1 (rs599839), 9p21.3/CDKN2A/2B (rs4977574), and 11q22.3/ PDGFD (rs974819)) in Koreans. From GWAS and a replication, SNP rs3782889 showed a strong association (combined P=3.95 10(-14)), although the association of SNP rs3782889 doesn't remain statistically significant after adjusting for SNP rs11066015 (proxy SNP with BRAP (r(2)=1)). But new possible CAD-associated variant was observed for rs9508025 (FLT1), even though its statistical significance did marginally reach at the genome-wide a significance level (combined P=6.07 10(-7)). This study shows that three CAD susceptibility loci, which were previously identified in European can be directly replicated in Koreans and also provides additional evidences implicating suggestive loci as risk variants for CAD in East Asian.</P>