Browsing by Subject "Genome-wide association studies"

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    Open Access
    Common variation neighbouring micro-RNA 22 is associated with increased left ventricular mass
    (Public Library of Science, 2013) Harper, Andrew R; Mayosi, Bongani M; Rodriguez, Antony; Rahman, Thahira; Hall, Darroch; Mamasoula, Chrysovalanto; Avery, Peter J; Keavney, Bernard D
    AIMS: Previous genome-wide linkage analysis has suggested that chromosomal region 17p13.3 may harbour genes influencing left ventricular mass (LVM) in man. To date, the genetic factors accounting for LVM variability remain largely unknown but a non-coding RNA gene within this region, micro-RNA 22 (miR-22) , has been implicated in cardiac hypertrophy and heart failure in animal models. We thus investigated the relationship between common genetic polymorphisms surrounding miR-22 and left ventricular mass in a family-based association study. Methods and RESULTS: We studied a cohort of 255 families comprising 1,425 individuals ascertained via a hypertensive proband. Ten single nucleotide polymorphisms which together tagged common genetic variation surrounding the miR-22 gene were genotyped. There was evidence of association between the rs7223247 polymorphism, which lies within the 3′UTR of a gene of unknown function, TLCD2, immediately downstream from miR-22, and left ventricular mass determined by Sokolow-Lyon voltage (Bonferroni corrected p- value = 0.038). The T allele at rs7223247 was associated with an 0.272 standard deviation higher Sokolow-Lyon voltage. Genotype was responsible for ∼1% of the population variability in LVM. CONCLUSIONS: Genotype at the rs7223247 polymorphism affects left ventricular mass determined by Sokolow-Lyon voltage. The neighbouring genes miR-22 and TLCD2 are strong candidates to account for this observation.
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    Determining ancestry proportions in complex admixture scenarios in South Africa using a novel proxy ancestry selection method
    (Public Library of Science, 2013) Chimusa, Emile R; Daya, Michelle; Möller, Marlo; Ramesar, Raj; Henn, Brenna M; van Helden, Paul D; Mulder, Nicola J; Hoal, Eileen G
    Admixed populations can make an important contribution to the discovery of disease susceptibility genes if the parental populations exhibit substantial variation in susceptibility. Admixture mapping has been used successfully, but is not designed to cope with populations that have more than two or three ancestral populations. The inference of admixture proportions and local ancestry and the imputation of missing genotypes in admixed populations are crucial in both understanding variation in disease and identifying novel disease loci. These inferences make use of reference populations, and accuracy depends on the choice of ancestral populations. Using an insufficient or inaccurate ancestral panel can result in erroneously inferred ancestry and affect the detection power of GWAS and meta-analysis when using imputation. Current algorithms are inadequate for multi-way admixed populations. To address these challenges we developed PROXYANC, an approach to select the best proxy ancestral populations. From the simulation of a multi-way admixed population we demonstrate the capability and accuracy of PROXYANC and illustrate the importance of the choice of ancestry in both estimating admixture proportions and imputing missing genotypes.
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    Integrative analysis of mRNA expression and half-life data reveals trans-acting genetic variants associated with increased expression of stable transcripts
    (Public Library of Science, 2013) Nguyen, Thong T; Seoighe, Cathal
    Genetic variation in gene expression makes an important contribution to phenotypic variation and susceptibility to disease. Recently, a subset of cis -acting expression quantitative loci (eQTLs) has been found to result from polymorphisms that affect RNA stability. Here we carried out a search for trans -acting variants that influence RNA stability. We first demonstrate that differences in the activity of trans -acting factors that stabilize RNA can be detected by comparing the expression levels of long-lived (stable) and short-lived (unstable) transcripts in high-throughput gene expression experiments. Using gene expression microarray data generated from eight HapMap3 populations, we calculated the relative expression ranks of long-lived transcripts versus short-lived transcripts in each sample. Treating this as a quantitative trait, we applied genome-wide association and identified a single nucleotide polymorphism (SNP), rs6137010, on chromosome 20p13 with which it is strongly associated in two Asian populations ( p =  4×10 −10 in CHB - Han Chinese from Beijing; p  = 1×10 −4 in JPT - Japanese from Tokyo). This SNP is a cis -eQTL for SNRPB in CHB and JPT but not in the other six HapMap3 populations. SNRPB is a core component of the spliceosome, and has previously been shown to affect the expression of many RNA processing factors. We propose that a cis -eQTL of SNRPB may be directly responsible for inter-individual variation in relative expression of long-lived versus short-lived transcript in Asian populations. In support of this hypothesis, knockdown of SNRPB results in a significant reduction in the relative expression of long-lived versus short-lived transcripts. Samples with higher relative expression of long-lived transcripts also had higher relative expression of coding compared to non-coding RNA and of RNA from housekeeping compared to non-housekeeping genes, due to the lower decay rates of coding RNAs, particularly those that perform housekeeping functions, compared to non-coding RNAs.
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    Partitioning the heritability of Tourette syndrome and obsessive compulsive disorder reveals differences in genetic architecture
    (Public Library of Science, 2013) Davis, Lea K; Yu, Dongmei; Keenan, Clare L; Gamazon, Eric R; Konkashbaev, Anuar I; Derks, Eske M; Neale, Benjamin M; Yang, Jian; Lee, S Hong; Evans, Patrick
    Author Summary Family and twin studies have shown that genetic risk factors are important in the development of Tourette Syndrome (TS) and obsessive compulsive disorder (OCD). However, efforts to identify the individual genetic risk factors involved in these two neuropsychiatric disorders have been largely unsuccessful. One possible explanation for this is that many genetic variations scattered throughout the genome each contribute a small amount to the overall risk. For TS and OCD, the genetic architecture (characterized by the number, frequency, and distribution of genetic risk factors) is presently unknown. This study examined the genetic architecture of TS and OCD in a variety of ways. We found that rare genetic changes account for more genetic risk in TS than in OCD; certain chromosomes contribute to OCD risk more than others; and variants that influence the level of genes expressed in two regions of the brain can account for a significant amount of risk for both TS and OCD. Results from this study might help in determining where, and what kind of variants are individual risk factors for TS and OCD and where they might be located in the human genome.
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    Pooled Sequencing of 531 Genes in Inflammatory Bowel Disease Identifies an Associated Rare Variant in BTNL2 and Implicates Other Immune Related Genes
    (Public Library of Science, 2015) Prescott, Natalie J; Lehne, Benjamin; Stone, Kristina; Lee, James C; Taylor, Kirstin; Knight, Jo; Papouli, Efterpi; Mirza, Muddassar M; Simpson, Michael A; Spain, Sarah L
    Author Summary Crohn's disease and ulcerative colitis are two forms of inflammatory bowel disease which cause chronic inflammation of the gastrointestinal tract. Common genetic variants in more than 160 regions of the human genome have been associated with an altered risk of these disorders, but leave much of the estimated genetic contribution to disease risk unexplained. We sought to establish whether rare genetic variants which alter the structure or function of the proteins encoded by genes also contribute to disease susceptibility. We used high throughput DNA sequencing to screen over 500 genes for such variants in nearly 500 patients and controls, and validated interesting variants in about 10,000 patients and 7,000 controls. We detected association of a limited number of rare variants from coding regions with disease, suggesting that they do not account for a large proportion of genetic susceptibility. However, they highlight the involvement of genes of potential importance in the development of inflammatory bowel disease, including those involved in the activation of immune cells, the regulation of immune response genes, and the degradation of proteins in cells.