SNPs and Other Features as They Predispose to Complex Disease: Genome-Wide Predictive Analysis of a Quantitative Phenotype for Hypertension

Though recently they have fallen into some disrepute, genome-wide association studies (GWAS) have been formulated and applied to understanding essential hypertension. The principal goal here is to use data gathered in a GWAS to gauge the extent to which SNPs and their interactions with other features can be combined to predict mean arterial blood pressure (MAP) in 3138 pre-menopausal and naturally post-menopausal white women. More precisely, we quantify the extent to which data as described permit prediction of MAP beyond what is possible from traditional risk factors such as blood cholesterol levels and glucose levels. Of course, these traditional risk factors are genetic, though typically not explicitly so. In all, there were 44 such risk factors/clinical variables measured and 377,790 single nucleotide polymorphisms (SNPs) genotyped. Data for women we studied are from first visit measurements taken as part of the Atherosclerotic Risk in Communities (ARIC) study. We begin by assessing non-SNP features in their abilities to predict MAP, employing a novel regression technique with two stages, first the discovery of main effects and next discovery of their interactions. The long list of SNPs genotyped is reduced to a manageable list for combining with non-SNP features in prediction. We adapted Efron's local false discovery rate to produce this reduced list. Selected non-SNP and SNP features and their interactions are used to predict MAP using adaptive linear regression. We quantify quality of prediction by an estimated coefficient of determination (R2). We compare the accuracy of prediction with and without information from SNPs

Homozygosity by descent mapping of blood pressure in the Old Order Amish: evidence for sex specific genetic architecture

<p>Abstract</p> <p>Background</p> <p>High blood pressure is a well established risk factor for morbidity and mortality acting through heart disease, stroke and cardiovascular disease. Genome wide scans have linked regions of nearly every human chromosome to blood pressure related traits. We have capitalized on beneficial qualities of the Old Order Amish of Lancaster, PA, a closed founder population with a relatively small number of founders, to perform a genome wide homozygosity by descent mapping scan. Each individual in the study has a non zero probability of consanguinity. Systolic and diastolic blood pressures are shown to have appreciable dominance variance components.</p> <p>Results</p> <p>Areas of two chromosomes were identified as suggestive of linkage to SBP and 5 areas to DBP in either the overall or sex specific analyses. The strongest evidence for linkage in the overall sample was to Chromosome 18q12 (LOD = 2.6 DBP). Sex specific analyses identified a linkage on Chromosome 4p12-14 (LOD in men only = 3.4 SBP). At Chromosome 2q32-33, an area where we previously reported significant evidence for linkage to DBP using a conventional identity by descent approach, the LOD was 1.4; however an appreciable sex effect was observed with men accounting for most of the linkage (LOD in men only = 2.6).</p> <p>Conclusion</p> <p>These results add evidence to a sex specific genetic architecture to blood pressure related traits, particularly in regions of linkage on chromosome 2, 4 and 18.</p

Identification of IGF1, SLC4A4, WWOX, and SFMBT1 as Hypertension Susceptibility Genes in Han Chinese with a Genome-Wide Gene-Based Association Study

Hypertension is a complex disorder with high prevalence rates all over the world. We conducted the first genome-wide gene-based association scan for hypertension in a Han Chinese population. By analyzing genome-wide single-nucleotide-polymorphism data of 400 matched pairs of young-onset hypertensive patients and normotensive controls genotyped with the Illumina HumanHap550-Duo BeadChip, 100 susceptibility genes for hypertension were identified and also validated with permutation tests. Seventeen of the 100 genes exhibited differential allelic and expression distributions between patient and control groups. These genes provided a good molecular signature for classifying hypertensive patients and normotensive controls. Among the 17 genes, IGF1, SLC4A4, WWOX, and SFMBT1 were not only identified by our gene-based association scan and gene expression analysis but were also replicated by a gene-based association analysis of the Hong Kong Hypertension Study. Moreover, cis-acting expression quantitative trait loci associated with the differentially expressed genes were found and linked to hypertension. IGF1, which encodes insulin-like growth factor 1, is associated with cardiovascular disorders, metabolic syndrome, decreased body weight/size, and changes of insulin levels in mice. SLC4A4, which encodes the electrogenic sodium bicarbonate cotransporter 1, is associated with decreased body weight/size and abnormal ion homeostasis in mice. WWOX, which encodes the WW domain-containing protein, is related to hypoglycemia and hyperphosphatemia. SFMBT1, which encodes the scm-like with four MBT domains protein 1, is a novel hypertension gene. GRB14, TMEM56 and KIAA1797 exhibited highly significant differential allelic and expressed distributions between hypertensive patients and normotensive controls. GRB14 was also found relevant to blood pressure in a previous genetic association study in East Asian populations. TMEM56 and KIAA1797 may be specific to Taiwanese populations, because they were not validated by the two replication studies. Identification of these genes enriches the collection of hypertension susceptibility genes, thereby shedding light on the etiology of hypertension in Han Chinese populations

Functional identification of the promoter of SLC4A5, a gene associated with cardiovascular and metabolic phenotypes in the HERITAGE Family Study

The sodium bicarbonate cotransporter gene SLC4A5, associated earlier with cardiovascular phenotypes, was tested for associations in the HERITAGE Family Study, and possible mechanisms were investigated. Twelve tag-single nucleotide polymorphisms (SNPs) covering the SLC4A5 gene were analyzed in 276 Black and 503 White healthy, sedentary subjects. Associations were tested using a variance components-based (QTDT) method with data adjusted for age, sex and body size. In Whites, rs6731545 and rs7571842 were significantly associated with resting and submaximal exercise pulse pressure (PP) (0.0004 <P<0.0007 and 0.002<P<0.003 respectively). Additionally, rs6731545 was associated with submaximal-exercise systolic blood pressure (SBP) and rate pressure product (P=0.002, both). New associations between rs6731545 and submaximal-exercise VO2 (P=0.003), rs7587117 and rs7571842 and VCO2 (0.0005<P<0.0009) and rs828853 and VE (P=0.002) were found. All these associations had a FDR<0.05. Single-marker associations were confirmed in haplotype analyses. Using in silico analysis, evidence was found for a main and an alternative promoter for SLC4A5. Specific promoter activity was experimentally confirmed using reporter constructs targeting both promoters in three physiologically relevant cell lines. Re-sequencing of 32 individuals having opposite homozygotes for rs7571842 and rs6731545 and exhibiting significantly different phenotypes showed no SNPs in the alternative promoter and no differences between the groups with SNPs in the main promoter. Also, of all known SLC4A5-coding SNPs, only one synonymous SNP was detected. Summarizing, the observed associations with resting and submaximal-exercise cardiovascular and metabolic traits in the HERITAGE Family Study are likely due to neither variation in the promoter nor known coding SNPs of SLC4A5