Browsing by Subject "Linkage Disequilibrium"

Now showing 1 - 16 of 16

Open Access
A Functional Polymorphism (rs2494752) in the AKT1 Promoter Region and Gastric Adenocarcinoma Risk in an Eastern Chinese Population.
(Scientific reports, 2016-01-28) Wang, Meng-Yun; He, Jing; Zhu, Mei-Ling; Teng, Xiao-Yan; Li, Qiao-Xin; Sun, Meng-Hong; Wang, Xiao-Feng; Yang, Ya-Jun; Wang, Jiu-Cun; Jin, Li; Wang, Ya-Nong; Wei, Qing-Yi
AKT is an important signal transduction protein that plays a crucial role in cancer development. Therefore, we evaluated associations between single nucleotide polymorphisms (SNPs) in the AKT promoter region and gastric cancer (GCa) risk in a case-control study of 1,110 GCa patients and 1,114 matched cancer-free controls. We genotyped five SNPs (AKT1 rs2494750G >C, AKT1 rs2494752A >G, AKT1 rs10138227C >T, AKT2 rs7254617G>A and AKT2 rs2304186G >T) located in the 5' upstream regulatory, first intron or promoter regions. In the logistic regression analysis, a significantly elevated GCa risk was associated with the rs2494752 AG/GG variant genotypes (adjusted odds ratio [OR] = 1.20, 95% confidence interval [CI] = 1.02-1.42) under a dominant genetic model, and this risk was more evident in subgroups of ever drinkers. The luciferase reporter assay showed that the rs2494752 G allele significantly increased luciferase activity. Our results suggest that the potentially functional AKT1 rs2494752 SNP may affect GCa susceptibility, likely by modulating the AKT1 promoter transcriptional activity. Larger, independent studies are warranted to validate our findings.
Open Access
An atlas connecting shared genetic architecture of human diseases and molecular phenotypes provides insight into COVID-19 susceptibility.
(Genome medicine, 2021-05) Wang, Liuyang; Balmat, Thomas J; Antonia, Alejandro L; Constantine, Florica J; Henao, Ricardo; Burke, Thomas W; Ingham, Andy; McClain, Micah T; Tsalik, Ephraim L; Ko, Emily R; Ginsburg, Geoffrey S; DeLong, Mark R; Shen, Xiling; Woods, Christopher W; Hauser, Elizabeth R; Ko, Dennis C
Background
While genome-wide associations studies (GWAS) have successfully elucidated the genetic architecture of complex human traits and diseases, understanding mechanisms that lead from genetic variation to pathophysiology remains an important challenge. Methods are needed to systematically bridge this crucial gap to facilitate experimental testing of hypotheses and translation to clinical utility.
Results
Here, we leveraged cross-phenotype associations to identify traits with shared genetic architecture, using linkage disequilibrium (LD) information to accurately capture shared SNPs by proxy, and calculate significance of enrichment. This shared genetic architecture was examined across differing biological scales through incorporating data from catalogs of clinical, cellular, and molecular GWAS. We have created an interactive web database (interactive Cross-Phenotype Analysis of GWAS database (iCPAGdb)) to facilitate exploration and allow rapid analysis of user-uploaded GWAS summary statistics. This database revealed well-known relationships among phenotypes, as well as the generation of novel hypotheses to explain the pathophysiology of common diseases. Application of iCPAGdb to a recent GWAS of severe COVID-19 demonstrated unexpected overlap of GWAS signals between COVID-19 and human diseases, including with idiopathic pulmonary fibrosis driven by the DPP9 locus. Transcriptomics from peripheral blood of COVID-19 patients demonstrated that DPP9 was induced in SARS-CoV-2 compared to healthy controls or those with bacterial infection. Further investigation of cross-phenotype SNPs associated with both severe COVID-19 and other human traits demonstrated colocalization of the GWAS signal at the ABO locus with plasma protein levels of a reported receptor of SARS-CoV-2, CD209 (DC-SIGN). This finding points to a possible mechanism whereby glycosylation of CD209 by ABO may regulate COVID-19 disease severity.
Conclusions
Thus, connecting genetically related traits across phenotypic scales links human diseases to molecular and cellular measurements that can reveal mechanisms and lead to novel biomarkers and therapeutic approaches. The iCPAGdb web portal is accessible at http://cpag.oit.duke.edu and the software code at https://github.com/tbalmat/iCPAGdb .
Open Access
Assessment of LD matrix measures for the analysis of biological pathway association.
(Stat Appl Genet Mol Biol, 2010) Crosslin, David R; Qin, Xuejun; Hauser, Elizabeth R
Complex diseases will have multiple functional sites, and it will be invaluable to understand the cross-locus interaction in terms of linkage disequilibrium (LD) between those sites (epistasis) in addition to the haplotype-LD effects. We investigated the statistical properties of a class of matrix-based statistics to assess this epistasis. These statistical methods include two LD contrast tests (Zaykin et al., 2006) and partial least squares regression (Wang et al., 2008). To estimate Type 1 error rates and power, we simulated multiple two-variant disease models using the SIMLA software package. SIMLA allows for the joint action of up to two disease genes in the simulated data with all possible multiplicative interaction effects between them. Our goal was to detect an interaction between multiple disease-causing variants by means of their linkage disequilibrium (LD) patterns with other markers. We measured the effects of marginal disease effect size, haplotype LD, disease prevalence and minor allele frequency have on cross-locus interaction (epistasis). In the setting of strong allele effects and strong interaction, the correlation between the two disease genes was weak (r=0.2). In a complex system with multiple correlations (both marginal and interaction), it was difficult to determine the source of a significant result. Despite these complications, the partial least squares and modified LD contrast methods maintained adequate power to detect the epistatic effects; however, for many of the analyses we often could not separate interaction from a strong marginal effect. While we did not exhaust the entire parameter space of possible models, we do provide guidance on the effects that population parameters have on cross-locus interaction.
Open Access
Associations between genetic variants in mRNA splicing-related genes and risk of lung cancer: a pathway-based analysis from published GWASs.
(Scientific reports, 2017-03-17) Pan, Yongchu; Liu, Hongliang; Wang, Yanru; Kang, Xiaozheng; Liu, Zhensheng; Owzar, Kouros; Han, Younghun; Su, Li; Wei, Yongyue; Hung, Rayjean J; Brhane, Yonathan; McLaughlin, John; Brennan, Paul; Bickeböller, Heike; Rosenberger, Albert; Houlston, Richard S; Caporaso, Neil; Teresa Landi, Maria; Heinrich, Joachim; Risch, Angela; Wu, Xifeng; Ye, Yuanqing; Christiani, David C; Amos, Christopher I; Wei, Qingyi
mRNA splicing is an important mechanism to regulate mRNA expression. Abnormal regulation of this process may lead to lung cancer. Here, we investigated the associations of 11,966 single-nucleotide polymorphisms (SNPs) in 206 mRNA splicing-related genes with lung cancer risk by using the summary data from six published genome-wide association studies (GWASs) of Transdisciplinary Research in Cancer of the Lung (TRICL) (12,160 cases and 16,838 controls) and another two lung cancer GWASs of Harvard University (984 cases and 970 controls) and deCODE (1,319 cases and 26,380 controls). We found that a total of 12 significant SNPs with false discovery rate (FDR) ≤0.05 were mapped to one novel gene PRPF6 and two previously reported genes (DHX16 and LSM2) that were also confirmed in this study. The six novel SNPs in PRPF6 were in high linkage disequilibrium and associated with PRPF6 mRNA expression in lymphoblastoid cells from 373 Europeans in the 1000 Genomes Project. Taken together, our studies shed new light on the role of mRNA splicing genes in the development of lung cancer.
Open Access
Detecting local haplotype sharing and haplotype association.
(Genetics, 2014-07) Xu, Hanli; Guan, Yongtao
A novel haplotype association method is presented, and its power is demonstrated. Relying on a statistical model for linkage disequilibrium (LD), the method first infers ancestral haplotypes and their loadings at each marker for each individual. The loadings are then used to quantify local haplotype sharing between individuals at each marker. A statistical model was developed to link the local haplotype sharing and phenotypes to test for association. We devised a novel method to fit the LD model, reducing the complexity from putatively quadratic to linear (in the number of ancestral haplotypes). Therefore, the LD model can be fitted to all study samples simultaneously, and, consequently, our method is applicable to big data sets. Compared to existing haplotype association methods, our method integrated out phase uncertainty, avoided arbitrariness in specifying haplotypes, and had the same number of tests as the single-SNP analysis. We applied our method to data from the Wellcome Trust Case Control Consortium and discovered eight novel associations between seven gene regions and five disease phenotypes. Among these, GRIK4, which encodes a protein that belongs to the glutamate-gated ionic channel family, is strongly associated with both coronary artery disease and rheumatoid arthritis. A software package implementing methods described in this article is freely available at http://www.haplotype.org.
Open Access
Detecting structure of haplotypes and local ancestry.
(Genetics, 2014-03) Guan, Yongtao
We present a two-layer hidden Markov model to detect the structure of haplotypes for unrelated individuals. This allows us to model two scales of linkage disequilibrium (one within a group of haplotypes and one between groups), thereby taking advantage of rich haplotype information to infer local ancestry of admixed individuals. Our method outperforms competing state-of-the-art methods, particularly for regions of small ancestral track lengths. Applying our method to Mexican samples in HapMap3, we found two regions on chromosomes 6 and 8 that show significant departure of local ancestry from the genome-wide average. A software package implementing the methods described in this article is freely available at http://bcm.edu/cnrc/mcmcmc.
Open Access
Generalized admixture mapping for complex traits.
(G3 (Bethesda), 2013-07-08) Zhu, Bin; Ashley-Koch, Allison E; Dunson, David B
Admixture mapping is a popular tool to identify regions of the genome associated with traits in a recently admixed population. Existing methods have been developed primarily for identification of a single locus influencing a dichotomous trait within a case-control study design. We propose a generalized admixture mapping (GLEAM) approach, a flexible and powerful regression method for both quantitative and qualitative traits, which is able to test for association between the trait and local ancestries in multiple loci simultaneously and adjust for covariates. The new method is based on the generalized linear model and uses a quadratic normal moment prior to incorporate admixture prior information. Through simulation, we demonstrate that GLEAM achieves lower type I error rate and higher power than ANCESTRYMAP both for qualitative traits and more significantly for quantitative traits. We applied GLEAM to genome-wide SNP data from the Illumina African American panel derived from a cohort of black women participating in the Healthy Pregnancy, Healthy Baby study and identified a locus on chromosome 2 associated with the averaged maternal mean arterial pressure during 24 to 28 weeks of pregnancy.
Open Access
Inter-chromosomal level of genome organization and longevity-related phenotypes in humans.
(Age (Dordr), 2013-04) Kulminski, Alexander M; Culminskaya, Irina; Yashin, Anatoli I
Studies focusing on unraveling the genetic origin of health span in humans assume that polygenic, aging-related phenotypes are inherited through Mendelian mechanisms of inheritance of individual genes. We use the Framingham Heart Study (FHS) data to examine whether non-Mendelian mechanisms of inheritance can drive linkage of loci on non-homologous chromosomes and whether such mechanisms can be relevant to longevity-related phenotypes. We report on genome-wide inter-chromosomal linkage disequilibrium (LD) and on chromosome-wide intra-chromosomal LD and show that these are real phenomena in the FHS data. Genetic analysis of inheritance in families based on Mendelian segregation reveals that the alleles of single nucleotide polymorphisms (SNPs) in LD at loci on non-homologous chromosomes are inherited as a complex resembling haplotypes of a genetic unit. This result implies that the inter-chromosomal LD is likely caused by non-random assortment of non-homologous chromosomes during meiosis. The risk allele haplotypes can be subject to dominant-negative selection primary through the mechanisms of non-Mendelian inheritance. They can go to extinction within two human generations. The set of SNPs in inter-chromosomal LD (N=68) is nearly threefold enriched, with high significance (p=1.6 × 10(-9)), on non-synonymous coding variants (N=28) compared to the entire qualified set of the studied SNPs. Genes for the tightly linked SNPs are involved in fundamental biological processes in an organism. Survival analyses show that the revealed non-genetic linkage is associated with heritable complex phenotype of premature death. Our results suggest the presence of inter-chromosomal level of functional organization in the human genome and highlight a challenging problem of genomics of human health and aging.
Open Access
Neuropeptide Y gene polymorphisms confer risk of early-onset atherosclerosis.
(PLoS Genet, 2009-01) Shah, SH; Freedman, NJ; Zhang, L; Crosslin, DR; Stone, DH; Haynes, C; Johnson, J; Nelson, S; Wang, L; Connelly, JJ; Muehlbauer, M; Ginsburg, GS; Crossman, DC; Jones, CJ; Vance, J; Sketch, MH; Granger, CB; Newgard, CB; Gregory, SG; Goldschmidt Clermont, PJ; Kraus, WE; Hauser, ER
Neuropeptide Y (NPY) is a strong candidate gene for coronary artery disease (CAD). We have previously identified genetic linkage to familial CAD in the genomic region of NPY. We performed follow-up genetic, biostatistical, and functional analysis of NPY in early-onset CAD. In familial CAD (GENECARD, N = 420 families), we found increased microsatellite linkage to chromosome 7p14 (OSA LOD = 4.2, p = 0.004) in 97 earliest age-of-onset families. Tagged NPY SNPs demonstrated linkage to CAD of a 6-SNP block (LOD = 1.58-2.72), family-based association of this block with CAD (p = 0.02), and stronger linkage to CAD in the earliest age-of-onset families. Association of this 6-SNP block with CAD was validated in: (a) 556 non-familial early-onset CAD cases and 256 controls (OR 1.46-1.65, p = 0.01-0.05), showing stronger association in youngest cases (OR 1.84-2.20, p = 0.0004-0.09); and (b) GENECARD probands versus non-familial controls (OR 1.79-2.06, p = 0.003-0.02). A promoter SNP (rs16147) within this 6-SNP block was associated with higher plasma NPY levels (p = 0.04). To assess a causal role of NPY in atherosclerosis, we applied the NPY1-receptor-antagonist BIBP-3226 adventitially to endothelium-denuded carotid arteries of apolipoprotein E-deficient mice; treatment reduced atherosclerotic neointimal area by 50% (p = 0.03). Thus, NPY variants associate with atherosclerosis in two independent datasets (with strong age-of-onset effects) and show allele-specific expression with NPY levels, while NPY receptor antagonism reduces atherosclerosis in mice. We conclude that NPY contributes to atherosclerosis pathogenesis.
Open Access
Novel associations of UDP-glucuronosyltransferase 2B gene variants with prostate cancer risk in a multiethnic study.
(BMC Cancer, 2013-11-22) Vidal, Adriana C; Tucker, Cocoa; Schildkraut, Joellen M; Richardson, Ricardo M; McPhail, Megan; Freedland, Stephen J; Hoyo, Cathrine; Grant, Delores J
BACKGROUND: We have previously shown that a functional polymorphism of the UGT2B15 gene (rs1902023) was associated with increased risk of prostate cancer (PC). Novel functional polymorphisms of the UGT2B17 and UGT2B15 genes have been recently characterized by in vitro assays but have not been evaluated in epidemiologic studies. METHODS: Fifteen functional SNPs of the UGT2B17 and UGT2B15 genes, including cis-acting UGT2B gene SNPs, were genotyped in African American and Caucasian men (233 PC cases and 342 controls). Regression models were used to analyze the association between SNPs and PC risk. RESULTS: After adjusting for race, age and BMI, we found that six UGT2B15 SNPs (rs4148269, rs3100, rs9994887, rs13112099, rs7686914 and rs7696472) were associated with an increased risk of PC in log-additive models (p < 0.05). A SNP cis-acting on UGT2B17 and UGT2B15 expression (rs17147338) was also associated with increased risk of prostate cancer (OR = 1.65, 95% CI = 1.00-2.70); while a stronger association among men with high Gleason sum was observed for SNPs rs4148269 and rs3100. CONCLUSIONS: Although small sample size limits inference, we report novel associations between UGT2B15 and UGT2B17 variants and PC risk. These associations with PC risk in men with high Gleason sum, more frequently found in African American men, support the relevance of genetic differences in the androgen metabolism pathway, which could explain, in part, the high incidence of PC among African American men. Larger studies are required.
Open Access
Polymorphisms in the ACE and ADRB2 genes and risks of aging-associated phenotypes: the case of myocardial infarction.
(Rejuvenation Res, 2010-02) Kulminski, Alexander M; Culminskaya, Irina V; Ukraintseva, Svetlana V; Arbeev, Konstantin G; Akushevich, Igor; Land, Kenneth C; Yashin, Anatoli I
Multiple functions of the beta2-adrenergic receptor (ADRB2) and angiotensin-converting enzyme (ACE) genes warrant studies of their associations with aging-related phenotypes. We focus on multimarker analyses and analyses of the effects of compound genotypes of two polymorphisms in the ADRB2 gene, rs1042713 and rs1042714, and 11 polymorphisms of the ACE gene, on the risk of such an aging-associated phenotype as myocardial infarction (MI). We used the data from a genotyped sample of the Framingham Heart Study Offspring (FHSO) cohort (n = 1500) followed for about 36 years with six examinations. The ADRB2 rs1042714 (C-->G) polymorphism and two moderately correlated (r(2) = 0.77) ACE polymorphisms, rs4363 (A-->G) and rs12449782 (A-->G), were significantly associated with risks of MI in this aging cohort in multimarker models. Predominantly linked ACE genotypes exhibited opposite effects on MI risks, e.g., the AA (rs12449782) genotype had a detrimental effect, whereas the predominantly linked AA (rs4363) genotype exhibited a protective effect. This trade-off occurs as a result of the opposite effects of rare compound genotypes of the ACE polymorphisms with a single dose of the AG heterozygote. This genetic trade-off is further augmented by the selective modulating effect of the rs1042714 ADRB2 polymorphism. The associations were not altered by adjustment for common MI risk factors. The results suggest that effects of single specific genetic variants of the ADRB2 and ACE genes on MI can be readily altered by gene-gene or/and gene-environmental interactions, especially in large heterogeneous samples. Multimarker genetic analyses should benefit studies of complex aging-associated phenotypes.
Open Access
Polymorphisms of TGFB1 and VEGF genes and survival of patients with gastric cancer.
(Journal of experimental & clinical cancer research : CR, 2009-06-30) Guan, Xiaoxiang; Zhao, Hui; Niu, Jiangong; Tan, Dongfeng; Ajani, Jaffer A; Wei, Qingyi
Some TGFB1 and VEGF polymorphisms are believed to be functional. Given that these genes are involved in tumor growth and progression including angiogenesis, dissemination, and invasiveness, we hypothesized that these polymorphisms would be associated with survival in patients with gastric cancer.We genotyped TGFB1 -509 C>T, +1869 T>C, and +915 G>C and VEGF -1498T>C, -634G>C, and +936C>T in 167 patients with gastric cancer. Using the Kaplan and Meier method, log-rank tests, and Cox proportional hazard models, we evaluated associations among TGFB1 and VEGF variants with overall, 1-year, and 2-year survival rates.Although there were no significant differences in overall survival rates among all polymorphisms tested, patients with TGFB1+915CG and CC genotypes had a poorer 2-year survival (adjusted hazard ratio (HR), 3.06; 95% confidence interval (CI), 1.09-8.62; P = 0.034) than patients with the GG genotype had. In addition, patients heterozygous for VEGF -634CG also had a poorer 1-year survival (adjusted HR, 2.08; 95% CI, 1.03-4.22; P = 0.042) than patients with the -634GG genotype.Our study suggested that TGFB1+915CG/CC and VEGF -634CG genotypes may be associated with short-term survival in gastric cancer patients. However, larger studies are needed to verify these findings.
Open Access
Potentially functional polymorphisms in the CASP7 gene contribute to gastric adenocarcinoma susceptibility in an eastern Chinese population.
(PloS one, 2013-01) Wang, Meng-Yun; Zhu, Mei-Ling; He, Jing; Shi, Ting-Yan; Li, Qiao-Xin; Wang, Ya-Nong; Li, Jin; Zhou, Xiao-Yan; Sun, Meng-Hong; Wang, Xiao-Feng; Yang, Ya-Jun; Wang, Jiu-Cun; Jin, Li; Wei, Qing-Yi
BACKGROUND: Caspase 7 (CASP7) is an important regulator and executioner in the apoptosis pathway and plays a crucial role in cancer development and progression. However, few studies have evaluated associations between functional single nucleotide polymorphisms (SNPs) in the 3' untranslational region (UTR) of CASP7 and risk of gastric cancer. METHODS: In a case-control study of 1117 patients with gastric cancer and 1146 cancer-free controls with frequency matching on age and sex, we genotyped four potentially functional SNPs (rs4353229T>C, rs10787498T>G, rs1127687G>A and rs12247479G>A) located in the microRNA binding sites of the CASP7 3' UTR by using Taqman assays and evaluated their associations with risk of gastric cancer by using logistic regression analyses as well as multifactorial dimension reduction (MDR) analysis. RESULTS: In the single-locus analysis, only the CASP7 rs4353229 TT genotype was associated with 0.83-fold decreased risk (95% confidence interval [CI] = 0.70-0.98) of gastric cancer under a recessive model, compared with the CT/CC genotypes. In the combined analysis of all four SNPs, we found that the risk of gastric cancer decreased by 19% in those carrying any of the risk genotypes (adjusted odds ratio = 0.81, 95% CI = 0.68-0.96), compared with those carrying zero risk genotypes, and this risk was more evident in subgroups of younger age (<59 years), females, non-smokers, non-drinkers and patients with non-gastric cardia adenocarcinoma. Further MDR analysis suggested some evidence of interactions between the combined genotypes and other risk factors for gastric cancer. CONCLUSIONS: Potentially functional CASP7 variants may contribute to risk of gastric cancer. Larger studies with different ethnic populations are warranted to validate our findings.
Open Access
Quantitative genetics of CTCF binding reveal local sequence effects and different modes of X-chromosome association.
(PLoS Genet, 2014-11) Ding, Zhihao; Ni, Yunyun; Timmer, Sander W; Lee, Bum-Kyu; Battenhouse, Anna; Louzada, Sandra; Yang, Fengtang; Dunham, Ian; Crawford, Gregory E; Lieb, Jason D; Durbin, Richard; Iyer, Vishwanath R; Birney, Ewan
Associating genetic variation with quantitative measures of gene regulation offers a way to bridge the gap between genotype and complex phenotypes. In order to identify quantitative trait loci (QTLs) that influence the binding of a transcription factor in humans, we measured binding of the multifunctional transcription and chromatin factor CTCF in 51 HapMap cell lines. We identified thousands of QTLs in which genotype differences were associated with differences in CTCF binding strength, hundreds of them confirmed by directly observable allele-specific binding bias. The majority of QTLs were either within 1 kb of the CTCF binding motif, or in linkage disequilibrium with a variant within 1 kb of the motif. On the X chromosome we observed three classes of binding sites: a minority class bound only to the active copy of the X chromosome, the majority class bound to both the active and inactive X, and a small set of female-specific CTCF sites associated with two non-coding RNA genes. In sum, our data reveal extensive genetic effects on CTCF binding, both direct and indirect, and identify a diversity of patterns of CTCF binding on the X chromosome.
Open Access
The genomic consequences of adaptive divergence and reproductive isolation between species of manakins.
(Mol Ecol, 2013-06) Parchman, TL; Gompert, Z; Braun, MJ; Brumfield, RT; McDonald, DB; Uy, JAC; Zhang, G; Jarvis, ED; Schlinger, BA; Buerkle, CA
The processes of adaptation and speciation are expected to shape genomic variation within and between diverging species. Here we analyze genomic heterogeneity of genetic differentiation and introgression in a hybrid zone between two bird species (Manacus candei and M. vitellinus) using 59 100 SNPs, a whole genome assembly, and Bayesian models. Measures of genetic differentiation (FST) and introgression (genomic cline center [α] and rate [β]) were highly heterogeneous among loci. We identified thousands of loci with elevated parameter estimates, some of which are likely to be associated with variation in fitness in Manacus populations. To analyze the genomic organization of differentiation and introgression, we mapped SNPs onto a draft assembly of the M. vitellinus genome. Estimates of FST, α, and β were autocorrelated at very short physical distances (< 100 bp), but much less so beyond this. In addition, average statistical associations (linkage disequilibrium) between SNPs were generally low and were not higher in admixed populations than in populations of the parental species. Although they did not occur with a constant probability across the genome, loci with elevated FST, α, and β were not strongly co-localized in the genome. Contrary to verbal models that predict clustering of loci involved in adaptation and isolation in discrete genomic regions, these results are consistent with the hypothesis that genetic regions involved in adaptive divergence and reproductive isolation are scattered throughout the genome. We also found that many loci were characterized by both exceptional genetic differentiation and introgression, consistent with the hypothesis that loci involved in isolation are also often characterized by a history of divergent selection. However, the concordance between isolation and differentiation was only partial, indicating a complex architecture and history of loci involved in isolation.
Open Access
Tissue-specific genetic control of splicing: implications for the study of complex traits.
(PLoS Biol, 2008-12-23) Heinzen, Erin L; Ge, Dongliang; Cronin, Kenneth D; Maia, Jessica M; Shianna, Kevin V; Gabriel, Willow N; Welsh-Bohmer, Kathleen A; Hulette, Christine M; Denny, Thomas N; Goldstein, David B
Numerous genome-wide screens for polymorphisms that influence gene expression have provided key insights into the genetic control of transcription. Despite this work, the relevance of specific polymorphisms to in vivo expression and splicing remains unclear. We carried out the first genome-wide screen, to our knowledge, for SNPs that associate with alternative splicing and gene expression in human primary cells, evaluating 93 autopsy-collected cortical brain tissue samples with no defined neuropsychiatric condition and 80 peripheral blood mononucleated cell samples collected from living healthy donors. We identified 23 high confidence associations with total expression and 80 with alternative splicing as reflected by expression levels of specific exons. Fewer than 50% of the implicated SNPs however show effects in both tissue types, reflecting strong evidence for distinct genetic control of splicing and expression in the two tissue types. The data generated here also suggest the possibility that splicing effects may be responsible for up to 13 out of 84 reported genome-wide significant associations with human traits. These results emphasize the importance of establishing a database of polymorphisms affecting splicing and expression in primary tissue types and suggest that splicing effects may be of more phenotypic significance than overall gene expression changes.

Browsing by Subject "Linkage Disequilibrium"

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