Genome Wide Association Study (GWAS)

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Lecture 7: Genome-wide Association Study

Lecture 7: Genome-wide Association Study

Genome-Wide Association Study (GWAS) — 27/37 — GWAS: independent single-variant tests across all genome-wide variants • Quality control (QC) of the study dataset • Choose a model/test for the phenotype of interest (e.g., linear regression model for quantitative traits, logistic regression model for dichotomous traits, other

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A genome-wide association study of bronchodilator response in asthmatics

A genome-wide association study of bronchodilator response in asthmatics

(CRHR)-2 locus, 10 and the adenylyl cyclase type 9 (AC9) gene. 11 A recent genome-wide association study (GWAS) of BDR by our group identified a functional variant in the serine- rich 2-like (SPATS2L) gene, albeit the mechanism by which it regulates BDR remains unknown. 12 In this manuscript, we expand on the previous literature by using a novel approach to identify genetic associations with BDR (defined by a change in lung function) whereby we apply five statistical models in a GWAS of this drug response phenotype to decrease the likelihood of false positive associations. Novel aspects of the current GWAS include use of genetic data from the parents of asthmatics in a family-based test, which is more robust against population stratification, as well as analysis of 11 BDR measures for each subject taken over a four year period in addition to BDR at randomization (taken upon entry into the clinical trial). Moreover, we considered both additive and recessive
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Genome-Wide Association Study of Polymorphisms Predisposing to Bronchiolitis.

Genome-Wide Association Study of Polymorphisms Predisposing to Bronchiolitis.

Bronchiolitis is a major cause of hospitalization among infants. Severe bronchiolitis is associated with later asthma, suggesting a common genetic predisposition. Genetic background of bronchiolitis is not well characterized. To identify polymorphisms associated with bronchiolitis, we conducted a genome- wide association study (GWAS) in which 5,300,000 single nucleotide polymorphisms (SNPs) were tested for association in a Finnish–Swedish population of 217 children hospitalized for bronchiolitis and 778 controls. The most promising SNPs (n = 77) were genotyped in a Dutch replication population of 416 cases and 432 controls. Finally, we used a set of 202 Finnish bronchiolitis cases to further investigate candidate SNPs. We did not detect genome-wide significant associations, but several suggestive association signals (p < 10 −5 ) were observed in the GWAS. In the replication population, three SNPs
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A Genome-Wide Association Study of a Biomarker of Nicotine Metabolism

A Genome-Wide Association Study of a Biomarker of Nicotine Metabolism

Abstract Individuals with fast nicotine metabolism typically smoke more and thus have a greater risk for smoking-induced diseases. Further, the efficacy of smoking cessation pharmacotherapy is dependent on the rate of nicotine metabolism. Our objective was to use nicotine metabo- lite ratio (NMR), an established biomarker of nicotine metabolism rate, in a genome-wide association study (GWAS) to identify novel genetic variants influencing nicotine metabo- lism. A heritability estimate of 0.81 (95% CI 0.70 –0.88) was obtained for NMR using mono- zygotic and dizygotic twins of the FinnTwin cohort. We performed a GWAS in cotinine- verified current smokers of three Finnish cohorts (FinnTwin, Young Finns Study, FIN- RISK2007), followed by a meta-analysis of 1518 subjects, and annotated the genome-wide significant SNPs with methylation quantitative loci (meQTL) analyses. We detected associ- ation on 19q13 with 719 SNPs exceeding genome-wide significance within a 4.2 Mb region. The strongest evidence for association emerged for CYP2A6 (min p = 5.77E-86, in intron 4), the main metabolic enzyme for nicotine. Other interesting genes with genome-wide signifi- cant signals included CYP2B6, CYP2A7, EGLN2, and NUMBL. Conditional analyses revealed three independent signals on 19q13, all located within or in the immediate vicinity of CYP2A6. A genetic risk score constructed using the independent signals showed associ- ation with smoking quantity (p = 0.0019) in two independent Finnish samples. Our meQTL results showed that methylation values of 16 CpG sites within the region are affected by genotypes of the genome-wide significant SNPs, and according to causal inference test, for some of the SNPs the effect on NMR is mediated through methylation. To our knowledge, this is the first GWAS on NMR. Our results enclose three independent novel signals on 19q13.2. The detected CYP2A6 variants explain a strikingly large fraction of variance (up to a11111
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Genome-Wide Association Study of Parity in Bangladeshi Women

Genome-Wide Association Study of Parity in Bangladeshi Women

As investigation of this hypothesis is novel, the findings presented here offer some insight into genetic variation and parity. Although our null GWAS doesn ’t rule out substantial herita- bility as it’s possible that many very weak effects could account for parity variation, overall, our findings are consistent with a low heritability of phenotypic variability for parity. In summary, our genome-wide association study of number of pregnancies and number of children in Ban- gladesh did not confer strong evidence of common variants for parity variation. However, our results suggest that future studies may want to consider the role of specific SNPs on chromo- somes 4, 5 and 6 in their analysis.
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Genome-Wide Association Study for Mid-Salt Tolerance in Rice

Genome-Wide Association Study for Mid-Salt Tolerance in Rice

ABSTRACT Salt stress is one of the environmental constraints that affect crop cultivation worldwide, since more than 800 Mha of land throughout the world suffer from salinization problems. Among cereals, rice (Oryza sativa L.) is one of the most sensitive to salt stress, although cultivars can differ in their response to salinity. In Europe, due to scarce water availability and the rise in sea levels, there is a clear tendency toward salinization in the river deltas where rice is grown. Thus, the identification of rice cultivars tolerant to salt stress and the dissection of salt stress tolerance mechanisms are of high interest for European rice breeding. Plant response to salt stress is a complex trait, depending on the combination of many genes and metabolic pathways, and thus difficult to control and engineer. Exploiting natural variation occurring in worldwide genotypes may be a powerful approach to discover new traits to tolerate high salinity conditions. In this context, a phenotyping activity has been performed to study the natural variation of a worldwide japonica rice collection in response to mid-salt stress. A greenhouse experiment was carried out on 281 japonica rice cultivars subjected to salt stress and the measurement of physiological traits (i.e. seedlings emergence rate, plant growth, chlorophyll fluorescence, flowering delay) was assessed. A genome wide association study (GWAS) highlighted the presence of significant loci involved in salt tolerance. Analysis of candidate genes significantly associated to these loci is in progress.
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A genome-wide association study of anorexia nervosa.

A genome-wide association study of anorexia nervosa.

Title: A genome-wide association study of anorexia nervosa. Authors: Boraska V, Franklin CS, Floyd JA, Thornton LM, Huckins LM, Southam L, Rayner NW, Tachmazidou I, Klump KL, Treasure J, Lewis CM, Schmidt U, Tozzi F, Kiezebrink K, Hebebrand J, Gorwood P, Adan RA, Kas MJ, Favaro A, Santonastaso P, Fernández-Aranda F, Gratacos M, Rybakowski F, Dmitrzak-Weglarz M, Kaprio J, Keski-Rahkonen A, Raevuori A, Van Furth EF, Slof-Op 't Landt MC, Hudson JI, Reichborn- Kjennerud T, Knudsen GP, Monteleone P, Kaplan AS, Karwautz A, Hakonarson H, Berrettini WH, Guo Y, Li D, Schork NJ, Komaki G, Ando T, Inoko H, Esko T, Fischer K, Männik K, Metspalu A, Baker JH, Cone RD, Dackor J, DeSocio JE, Hilliard CE, O'Toole JK, Pantel J, Szatkiewicz JP, Taico C, Zerwas S, Trace SE, Davis OS, Helder S, Bühren K,
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Semantically enabling a genome-wide association study database

Semantically enabling a genome-wide association study database

16. Hughes LM, Bao J, Hu ZL, Honavar V, Reecy JM: Animal trait ontology: The importance and usefulness of a unified trait vocabulary for animal species. J Anim Sci 2008, 86(6):1485 – 1491. 17. Newton-Cheh C, Johnson T, Gateva V, Tobin MD, Bochud M, Coin L, Najjar SS, Zhao JH, Heath SC, Eyheramendy S, Papadakis K, Voight BF, Scott LJ, Zhang F, Farrall M, Tanaka T, Wallace C, Chambers JC, Khaw KT, Nilsson P, van der Harst P, Polidoro S, Grobbee DE, Onland-Moret NC, Bots ML, Wain LV, Elliott KS, Teumer A, Luan J, Lucas G, et al: Genome-wide association study identifies eight loci associated with blood pressure. Nat Genet 2009, 41(6):666 – 676.
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Genome wide association study of Alzheimer's disease with psychotic symptoms

Genome wide association study of Alzheimer's disease with psychotic symptoms

Genome-wide Association Study of Alzheimer’s disease with Psychotic Symptoms Paul Hollingworth 1,16 , Robert A. Sweet 2,3,4,16,* , Rebecca Sims 1,16 , Denise Harold 1 , Giancarlo Russo 1 , Richard Abraham 1 , Alexandra Stretton 1 , Nicola Jones 1 , Amy Gerrish 1 , Jade Chapman 1 , Dobril Ivanov 1 , Valentina Moskvina 1 , Simon Lovestone 5 , Petroula Priotsi 5 , Michelle Lupton 5 , Carol Brayne 6 , Michael Gill 7 , Brian Lawlor 7 , Aoibhinn Lynch 7 , David Craig 8 , Bernadette McGuinness 8 , Janet Johnston 8 , Clive Holmes 9 , Gill Livingston 10 , Nicholas J. Bass 10 , Hugh Gurling 10 , Andrew McQuillin 10 , GERAD Consortium11, the National Institute on Aging Late-Onset Alzheimer’s Disease Family Study Group12, Peter Holmans 1 , Lesley Jones 1 , Bernie Devlin 2 , Lambertus Klei 2 , M. Michael Barmada 14 , F.
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TDT for Human QTL Mapping and Genome - Wide Association Study

TDT for Human QTL Mapping and Genome - Wide Association Study

Furthermore, though the TDT approach used for gene mapping at multi loci has been studied by a number of researchers recently, the application of TDT to genome- wide association study has not been tackled so far. Since the rapid improvement in SNP genotyping technology makes it possible to find the genetic contributions to common disease, in this thesis we develop a generalized TDT by a penalized logistic model to extend the TDT to genome-wide association study. By virtue of this model, we convert the linkage study for gene mapping to variable selection problem. A two-step method which combines the e fficient algorithm for variables selection with a new criterion for model selection is proposed. In the simulation study, by comparing the false discovery rate and positive selection rate with the Bonferroni-type multiple-comparison approach, it is demonstrated that our method is valid and e fficient.
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A Genome-Wide Association Study for Regulators of Micronucleus Formation in Mice

A Genome-Wide Association Study for Regulators of Micronucleus Formation in Mice

ABSTRACT In mammals the regulation of genomic instability plays a key role in tumor suppression and also controls genome plasticity, which is important for recombination during the processes of immunity and meiosis. Most studies to identify regulators of genomic instability have been performed in cells in culture or in systems that report on gross rearrangements of the genome, yet subtle differences in the level of genomic instability can contribute to whole organism phenotypes such as tumor predisposition. Here we performed a genome-wide association study in a population of 1379 outbred Crl:CFW(SW)-US_P08 mice to dissect the genetic landscape of micronucleus formation, a biomarker of chromosomal breaks, whole chromosome loss, and extranuclear DNA. Variation in micronucleus levels is a complex trait with a genome- wide heritability of 53.1%. We identify seven loci influencing micronucleus formation (false discovery rate ,5%), and define candidate genes at each locus. Intriguingly at several loci we find evidence for sexual dimorphism in micronucleus formation, with a locus on chromosome 11 being specific to males.
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A genome-wide association study for corneal astigmatism: The CREAM Consortium

A genome-wide association study for corneal astigmatism: The CREAM Consortium

17. Li Q, Wojciechowski R, Simpson CL, Hysi PG, Verhoeven VJ, Ikram MK, Hohn R, Vitart V, Hewitt AW, Oexle K, Makela KM, MacGregor S, Pirastu M, Fan Q, Cheng CY, St Pourcain B, McMahon G, Kemp JP, Northstone K, Rahi JS, Cumberland PM, Martin NG, Sanfilippo PG, Lu Y, Wang YX, Hayward C, Polasek O, Campbell H, Bencic G, Wright AF, Wedenoja J, Zeller T, Schillert A, Mirshahi A, Lackner K, Yip SP, Yap MK, Ried JS, Gieger C, Murgia F, Wilson JF, Fleck B, Yazar S, Vingerling JR, Hofman A, Uitterlinden A, Rivadeneira F, Amin N, Karssen L, Oostra BA, Zhou X, Teo YY, Tai ES, Vithana E, Barathi V, Zheng Y, Siantar RG, Neelam K, Shin Y, Lam J, Yonova-Doing E, Venturini C, Hosseini SM, Wong HS, Lehtimaki T, Kahonen M, Raita- kari O, Timpson NJ, Evans DM, Khor CC, Aung T, Young TL, Mitchell P, Klein B, van Duijn CM, Meitinger T, Jonas JB, Baird PN, Mackey DA, Wong TY, Saw SM, Parssinen O, Stambolian D, Hammond CJ, Klaver CC, Williams C, Paterson AD, Bailey-Wilson JE, Guggenheim JA. Cream Consortium. Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error: the CREAM consortium. Hum Genet 2015; 134:131-46. .
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A genome-wide association study on medulloblastoma.

A genome-wide association study on medulloblastoma.

carriers of the risk allele had a more than two-fold increased risk. Our findings were not statistically significant when using the p value threshold p < 5 × 10 –8 to correct for mul- tiple comparisons. Although a stringent p-value threshold is required in GWAS to reduce the presence of false posi- tive findings, strict Bonferroni correction may be considered overly conservative due to linkage disequilibrium between many genetic variants. Twelve variants with evidence for associations in the initial analyses were investigated in an additional cohort. One of these SNPs, located in 18p11.23 (PTPRM) showed suggestive evidence for an association with medulloblastoma risk also in the validation cohort. The PTPRM gene product is a receptor-type protein tyros- ine phosphatase that mediates cell–cell adhesion. Altered expression, mutations, or aberrant methylation of PTPRM have been described in different malignancies, including glioblastoma [ 9 ]. The role of PTPRM in medulloblastoma is, to our knowledge, unknown, but it is interesting to note that the PTPRM protein has been shown to interact with beta- catenin [ 10 ]. Beta-catenin is a central part of the Wnt signal- ing pathway and is encoded by the gene CTNNB1, which is frequently mutated in WNT medulloblastoma [ 5 ]. However, only about 10% of all medulloblastoma tumors belong to the WNT subgroup [ 5 ], and this subgroup is therefore rep- resented by few patients in the study cohort. Investigation of
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A Genome Wide Association Study for  Longevity in Cattle

A Genome Wide Association Study for Longevity in Cattle

Figure 3. Quantile-quantile plots for single SNP GWAS results without (left) and with (right) correction for population structure. For the 4887 animals and 33,556 SNPs in our study, 14 SNPs were marked as significant using local false discovery rate and 67 SNPs when using the q-value threshold. The 14 fdr SNPs were the most significant SNPs from the larger set (Figure 2) on chromosomes 6, 13, 14, 19 and 21. The 67 selected SNPs based one the q- value threshold was spread out on 19 chromosomes, with many chromosomes having only one or two significant SNPs. The selected regions were cross validated with the NCBI data base to search for genes of interest.
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Progress of genome wide association study in domestic animals

Progress of genome wide association study in domestic animals

Conclusions In summary, there was a great progress of GWAS in do- mestic animals and some genes for economically import- ant traits have been identified. However, the main problem lies in the inconsistencies among the results of these GWAS reports for the same trait, which may be mainly attributed to many aspects such as population size, density of the markers (SNPs), population genetic structure, choice of statistical models, as well as type I and II errors. To achieve the accurate estimation of SNP effects on traits of interest in a GWAS, larger population size and higher density of the markers (SNPs) were required. Currently, SNP chips were widely applied in GWAS and enhanced the identification of QTL for traits of interest in domestic animals. Compared with SNP chips, sequencing could provide nearly all information about the variations, including SNP, copy number vari- ation (CNV) and the deletion/insertion, et al., on the whole genome in detected population. Along with the reduction in sequencing cost, it is possible that all indivi- duals in the tested populations might be sequenced and genotyped and GWAS might be carried out in this plat- form then. In the future, GWAS in domestic animals will focus on the identification of causative mutations for economically important traits. The findings will inev- itably facilitate the understanding of the genetic archi- tecture of complex traits in domestic animals and practical improving the breeding programmes.
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Genome wide association study for multiple phenotype analysis

Genome wide association study for multiple phenotype analysis

Discussion and conclusions The explosion in datacollection and the increasing evidence that some loci affect multiple traits require more complex statistical models for analyses to better under- stand the properties of association. Here, we reviewed several different methods for multiple phenotypes in GWAS, and expanded the USAT approach to related sam- ples as pUSAT. The proposed method can provide insight into the underlying associations, and help the researchers to identify pleiotropic loci especially when prior informa- tion is unavailable. The simulation studies demonstrate that the Type I error rate of pUSAT is conservative under different correlations. We also applied various methods to the GAW20 data with TG and HDL-C as the phenotypes.
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A genome-wide association study in multiple system atrophy

A genome-wide association study in multiple system atrophy

Conclusions: We present a GWAS in MSA. We have identified several potentially interesting gene loci, including the MAPT locus, whose significance will have to be evaluated in a larger sample set. Common genetic variation in SNCA and COQ2 does not seem to be associated with MSA. In the future, additional samples of well-characterized patients with MSA will need to be collected to perform a larger MSA GWAS, but this initial study forms the basis for these next steps. Neurology ® 2016;87:1591 – 1598

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Genome-wide association study of male sexual orientation

Genome-wide association study of male sexual orientation

Study Sample. We obtained institutional review board approval from NorthShore University HealthSystem, and after a study description all enrolled subjects gave informed consent. All methods were performed in accord- ance with the relevant guidelines and regulations. Our GWAS analyzed sample of primarily European ancestry men included a total of 1,077 homosexual and 1,231 heterosexual men, comprised as follows. In our GWLS on 409 pairs of homosexual brothers in 384 multiplex families 23 , we classified men as homosexual based on

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Genome-wide association study in Guillain-Barré syndrome

Genome-wide association study in Guillain-Barré syndrome

Guillain-Barré syndrome (GBS) is considered to have an immune-mediated basis, but the genetic contribution to GBS is unclear. We conducted a GWAS involving 215 GBS patients and 1,105 healthy controls. No significant associations of individual SNPs or imputed HLA types were observed. We performed a genome-wide complex trait analysis for evaluation of the heritability of GBS, and found that common SNPs contribute up to 25% of susceptibility to the disease. Genetic risk score analysis showed no evidence of overlap in genetic susceptibility factors of GBS and multiple sclerosis. Given the unexplained heritability of the trait further larger GWAS are indicated.
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Genome-wide association study of antisocial personality disorder

Genome-wide association study of antisocial personality disorder

identical genotypes as the GWAS genotyping with 499% concordance between the two methods. In a post hoc repeat GWAS analysis, including the CRIME subjects and GenMets controls, the results were consistent with the original analysis. This also indicated that had there been discrepancy with the Corogene control sample genotypes of the eight SNPs in the GWAS, this would have shown in the repeat analysis results. In spite of intensive QC, spurious associations may occur. We considered the top variant (rs6462756, near SDK1 gene) of the analysis of males and females combined as a plausible false positive, as it was the only signal from that genomic region (7p22.2), where the SNP density was not particularly sparse, rather to the contrary, relatively dense (35 SNPs per 100 kb, compared with chr 7p average 21 SNPs per 100 kb and the nearby 500 kb average 25 SNPs per 100 kb), and thus, it was not selected to the regenotyping nor to the replication study.
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