Genome-Wide Association Studies with Single Nucleotide Polymorphisms (SNPs), Copy Number Variations (CNVs), and Gene Expression Profiles to Find Genetic Markers for Young-Onset Hypertension in Taiwan Han Chinese

• Main Authors: Kuang-Mao Chiang, 姜廣茂
• Other Authors: Wen-Harn Pan
• Format: Others
• Language: en_US
• Published: 2014
• Online Access: http://ndltd.ncl.edu.tw/handle/jehx3x

博士 === 國防醫學院 === 生命科學研究所 === 102 === Hypertension is an important public health problem in Taiwan and in the world. Although many large-scale genome-wide association studies (GWAS) have been performed, few study identified replicable and large-impact hypertension loci, not to mention the scanty Chinese studies. Young onset hypertension (YOH) is considered as a more promising target disorder to investigate than the late-onset one due to its stronger genetic component. To map YOH genetic variants, we carried out GWAS to search for hypertension susceptibility loci/genes with whole genome SNPs, CNVs and gene expression profiles. This investigation was consisted of 3 studies. The first part is a three-stage genome-wide association study using SNPs as genetic markers (SNPs-GWAS), combining 1st-stage multilocus GWAS (400 age- and sex-matched pairs), 2nd-stage gene expression analysis, and 3rd-stage multilocus confirmatory study (992 matched pairs). The second part is a two-stage genome-wide CNVs association study (CNVs-GWAS) consisting of an usual first stage GWAS (200 matched pairs) to find potential susceptibility CNV regions and a second stage confirmatory association study with an independent set of samples (199 matched pairs). Gene expression profiles were used to find differentially expressed genes among those implicated in both the first and second stages of the study. The third part is a two-stage genome-wide gene expression association study (GEs-GWAS), consisting of a regular GWAS in the 1st - stage (126 YOHs and 149 controls) to find the differentially expressed genes and a further confirmation with an independent set of samples (127 YOHs and 150 controls). We also integrated the gene expression data and SNP data to find eSNPs. In the SNPs-GWAS, a total of six SNP septets flanking the C1orf135, GSN, LARS, and ACTN4 remained significant in all three stages. Among them, the septet flanking ACTN4 and LARS was also associated with blood pressure/hypertension in two external replication studies: Hong Kong Hypertension Study (HKHS) and WTCCC hypertension study. In the CNVs-GWAS, 11 CNVs regions involving 14 genes were identified. In the GEs-GWAS, 9 genes were significantly associated with hypertension in both the first- and second-stage. Among these genes, ZRANB1, FAM110A, PREP, ANKRD9 and LAM2 were also differentially expressed in an existing database of hypertensive mouse model (GSE19817). Our study identified several previously unknown YOH loci/genes in Han Chinese. Identification of these genes enriches hypertension susceptibility gene list, thereby shedding light on the etiology of hypertension in Han Chinese.