Genetic Epidemiology Core Laboratory

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1 2012 CGM Report Genetic Epidemiology Core Laboratory 卓 越 成 員 Remarkable member Wei J. Chen 陳 為 堅 Professor/ / EDUCATION AND POSITION HELD Bachelor of Medicine, College of Medicine, National Taiwan University, Master of Science, Departments of Behavioral Sciences and Epidemiology, Harvard School of Public Health, Doctor of Science, Department of Epidemiology, Harvard School of Public Health, ; Post-doc, Professor, Department of Public Health &Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, 1997-Present Distinguished Professor, National Taiwan University, 2007-Present Dean, College of Public Health, National Taiwan University, 2011-Present HONOR Excellent Research Award, National Science Council, Taiwan, Outstanding Young Persons, The 35th, Junior Chamber International in Taiwan, 1997 The 11th Ching-Hsing Medical Award, 2000, Ching-Hsing Foundation, Taiwan, 2000 Outstanding Research Award (3-year award), & , National Science Council, Taiwan Distinguished Professor, 2007-present, National Taiwan University RESEARCH INTERESTS Psychiatric and genetic epidemiology of schizophrenia Genetic epidemiology of metabolic dysfunction Application of genomic medicine SELECTED PUBLICATION Lien YJ, Liu CM, Faraone SV, Tsuang MT, Hwu HG, Hsiao PC, Chen WJ. A genome-wide quantitative trait loci scan of neurocognitive performances in families with schizophrenia. Genes Brain Behav. 2010, 9: Lai CY, Yu SL, Hsieh MH, Chen CH, Chen HY, Wen CC, Huang YH, Hsiao PC, Hsiao CK, Liu CM, Yang PC, Hwu HG, Chen WJ. MicroRNA expression aberration as potential peripheral blood biomarkers for schizophrenia. PLoS ONE. 2011, 6: e Wang SH, Hsiao PC, Hsiao CK, Liu PH, Chien KL, Lin SR, Lee WC, Chen WJ. Multilevel analysis of habitual physical activity and metabolic syndrome in northern Taiwan. Prev Med. 2011, 53: Lien YJ, Hsiao PC, Liu CM, Faraone SV, Tsuang MT, Hwu HG, Chen WJ. A genome-wide linkage scan for distinct subsets of schizophrenia characterized by age at onset and neurocognitive deficits. PLoS ONE. 2011, 6(8): e

2 Genetic Epidemiology Core Laboratory 卓 越 成 員 Remarkable member Kuo-Liong Chien Professor/ EDUCATION AND POSITION HELD 簡 國 龍 M.D., Department of Medicine, National Taiwan University ( ) Ph.D., Section of Preventive Medicine, Institute of Epidemiology, School of Public Health, National Taiwan University ( ) Associate Professor, Institute of Preventive Medicine, College of Public Health, National Taiwan University ( ) Attending Physician, Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital (since 1995) Professor, Institute of Epidemiology & Preventive Medicine, College of Public Health, National Taiwan University (since 2010) Director, Institute of Epidemiology & Preventive Medicine, College of Public Health, National Taiwan University (since 2011) NTU CGM HONOR Excellent Research Award, NTU, 2008, 2009, 2010 RESEARCH INTERESTS Genetic Epidemiology Cardiovascular Epidemiology Clinical Trials Hyperlipidemia & Atherosclerosis Mechanisms SELECTED PUBLICATION Genetic Epidemiology Core Laboratory KL Chien, HJ Lin, BC Lee, HC Hsu, YT Lee, MF Chen: A Prediction Model for the Risk of Incident Chronic Kidney Disease. American Journal of Medicine, 2010, 123: KL Chien, Wang KC, Chen YC, Chao CL, Hsu HC, Chen MF, Chen WJ. Common sequence variants in pharmacodynamic and pharmacokinetic pathway-related genes conferring LDL cholesterol response to statins. Pharmacogenomics. 2010, 11: KL Chien, TC Su, HC Hsu, WT Chang, PC Chen, FC Sung, MF Chen YT Lee: Constructing the Prediction Model for the Risk of Stroke in Chinese: Report from a Cohort Study in Taiwan. Stroke, 2010, 41(9): KL Chien, CL Chao, CH Kuo, HJ Lin, PH Liu, PR Chen, HC Hsu, BC Lee, YT Lee, MF Chen: Plasma Fatty Acids and the Risk of Metabolic Syndrome in Ethnic Chinese Adults in Taiwan. Lipids in Health and Disease, 2011, 10:33. KL Chien, YK Tu, HC Hsu, TC Su, YT Lee, MF Chen: Partial least squares analysis of the association between metabolic factors and left ventricular mass among Taiwanese adolescents, International Journal of Cardiology, 2011, 147(2):

3 2012 CGM Report Remarkable result CHEN, WEI J. Chien, Kuo-Liong On the basis of a variety of study samples, genotyping equipment, and software for genetic epidemiological analysis that have been successfully installed in this core laboratory, the specific aims of this Core Laboratory can be summarized as follows: (1) to provide large samples for association studies of the search for the susceptibility genes of complex diseases, including community-based case-controls and nuclear families of simplex or multiplex probands; (2) to facilitate whole genome association studies based on either population case-control design or family-based association design; (3) to provide service for the genotyping of genetic variants; (4) to provide updated genetic epidemiological analyses for researchers who have the data but encounter difficulty in making full utilization of it and (5) to develop new methods for relevant genetic analysis. The core labratory aims to: (1) facilitate genetic epidemiological studies within the campus by means of active promotion, workshop, and collaboration; (2) help identify important genetic variants as well as contextual variables that influence the risk of metabolic syndrome in a community sample of large sample size; (3) help the gene mapping for schizophrenia by means of familybased association as well as schizophrenia-related endophenotype in non-clinical samples; (4) help train more students and research assistants who can deal with genetic epidemiology via hands-on experience; and (5) help researchers accomplish their genetic epidemiological investigation of the diseases they are interested in. We have gradually worked out some collaborating modules in providing help to researchers in conducting their genetic epidemiological research, and we can provide service in the statistical analysis for the data of pedigree, sib-pair, and case-control studies, such as linkage, association, and linkage disequilibrium analysis. The service of genetic data analysis that we presently provide can be illustrated by the following examples of genetic study 1. Linkage and association analysis of schizophrenia or schizophrenia related traits studies 1 A genome-wide quantitative linkage scan of niacin skin flush response in families with schizophrenia Collected siblings and their relatives of 115 families for quantitative trait loci linkage analysis. Nonparametric linkage z (NPL-Z) scores were calculated for each of 386 microsatellite markers spaced at an average of 9-cMintervals. Niacin patches of three concentrationswere applied to forearm skin, and the flush response was rated at 5, 10, and 15 minutes, respectively, with a 4-point scale. Determination of genome-wide empiricalsignificance was implemented using 1,000 simulated genome scans. One linkage peak attaining genome-wide significancewas identified at chromosomal region 14q32.12 for 0.01M concentration at 5 minutes. The finding indicates that there might be modifier or susceptibility-modifier genes at 14q32.12 for schizophrenia-related attenuation of flush response to niacin. 52

4 2Family genetic study using ordered linkage analysis This study aimed to identify more homogeneous subgroups of families for fine mapping on regions around markers D6S296 and D6S309 (both in 6p24.3) as well as D6S274 (in 6p22.3) by means of similarity in neurocognitivefunctioning. A total of 160 families of patients with schizophrenia comprising at least two affected siblings who had data for 8 neurocognitive test variables of the Continuous Performance Test (CPT) and the Wisconsin Card Sorting Test (WCST) were subjected to cluster analysis with data visualization using the test scores of both affected siblings. After adjustment using false discovery rate for multiple testing, SNP rs13873 and haplotype rs rs13873 on BMP6-TXNDC5 genes were significantly associated with schizophrenia for the deficit cluster 1 but not for the deficit cluster 2 or non-deficit cluster. Our results provide further evidence that the BMP6-TXNDC5 locus on 6p24.3 may play a role in the selective impairments on sustained attention of schizophrenia. Figure 1. Linkage plots for the niacin flush response with 0.01M at 5 minutes on chromosome 14 along with the corresponding linkage results based on the diagnosis of schizophrenia. (Lien YJ et al, Schizophrenia Bulletin 2011) Figure 2. Results of family-based clustering analysis by means of the mean adjusted z scores of the affected siblings for each family. (Lin SH et al, Genes Brain Behav. 2009) 3MicroRNA expression aberration as potential peripheral blood biomarkers for schizophrenia This study aimed to identify potential mirna signature for schizophrenia by comparing genomewide mirna expression profiles in patients with schizophrenia vs. healthy controls. A genomewide mirna expression profiling was performed using a Taqman array of 365 human mirnas in the mononuclear leukocytes of a learning set of 30 cases and 30 controls. The discriminating performance of potential biomarkers was validated in an independent testing set. A seven-mirna signature (hsa-mir-34a, mir-449a, mir-564, mir-432, mir-548d, mir-572 and mir-652) was derived from a supervised classification with internal cross-validation. The putative signature was then validated in the testing set. These mirnas were differentially correlated with patients negative symptoms, neurocognitive performance scores, and event-related potentials. The results indicated that the mononuclear leukocyte-based mirna profiling is a feasible way to identify biomarkers for schizophrenia, and the seven-mirna signature warrants further investigation. NTU CGM Genetic Epidemiology Core Laboratory 53

5 2012 CGM Report 2.Pharmacogeomics study This study assessed the association between pharmacokinetic- and pharmacodynamics- related genes and individual responses to LDL lowering by statins in a Chinese population. A total of 386 patients with primary hypercholesterolemia were treated with statin for nine months in a hospitalbased case-only study. The 62 haplotype-tagging single nucleotide polymorphisms of 10 candidate genes were genotyped. Treating LDL-C reduction as an outcome variable, we performed multiple linear regression models in various modes of inheritance to test the effects of SNP and haplotype variants. Our results indicated a strong association of sequence variants of HMGCR, SREBF1 and ABCG8 genes with the reduction of LDL-C after statin treatment in a Chinese population. Future studies on genes of drug metabolism enzymes and transporters are warranted. (Chien KL et al, Pharmacogenomics 2010) 3.Metabolic dysfunction study This study aimed to investigate potential mechanisms underlying the associations of rs with type 2 diabetes (T2D). Eighteen SNPs were tested for association with glucose/insulin homeostasis as well as other quantitative metabolic phenotypes using the quantitative transmission disequilibrium test (QTDT) in 525 Taiwanese adolescent twin-pairs and siblings. The results were further replicated in 116 non-diabetic normotensive Caucasian young adults. Among the 18 SNPs, rs C allele was significantly associated with higher glucose concentrations, higher insulin concentrations, and a lower insulin sensitivity index, but was not associated with insulin secretion. The findings support an important role for T2D risk-conferring gene TCF7L2 in insulin resistance in both Taiwanese and Caucasian youth, and underscore the emerging role of Wnt signaling in insulin resistance. Figure 3. A comparison of: (A) the TLDA-based mirna expression levels between the schizophrenia patients (n = 30) and the controls (n = 30) for the seven mirnas; and (B) quantitative RT-PCR-based mirna expression levels between the schizophrenia patients (n = 60) and the controls (n = 30) for the same seven mirnas. (Source: Lai, C.-Y., et al., PLoS ONE. 6(6): p. e21635, 2011) 54

6 NTU CGM Figure 4. (1)The association of TCF7L2 SNPs with quantitative metabolic phenotypes. The position (kb) indicates chromosomal position relative to the transcription start site of TCF7L2. (2)Plasma glucose and insulin levels during OGTTs according to rs genotypes in 525 nondiabetic adolescent twinpairs and siblings. (Liu PH et al., J. Clin. Endocr.Metab. 94(9): , 2009.) Core Service Equipment: -86C refrigerator, -195C liquid nitrogen storage system Sample Storage: DNA, plasma, serum, buffy coat, whole blood, cell line SNP markers, gene expression assay Data type: pedigree data, sib-pair data, case-control data, trio data Analysis: linkage analysis, association study (TDT, case-control study), linkage disequilibrium analysis, genome-wide linkage scan, genome-wide association analysis Clinical sample, community sample, youth sample Platform for mirna experiment Genetic Epidemiology Core Laboratory Genetic data process, genetic/epidemiological database, statistical graph/chart process, genetic statistical programming/scripts Genetic epidemiological seminar, symposium, workshop, experimental training course 55

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