Association Studies: A genome-wide association approach to mapping the genetic determinants of the transcriptome in human populations

Selection by means of genetic markers is a promising approach to the eradication of infectious diseases in farm animals, especially in the absence of eﬀective methods of treatment and prevention. Bovine leukemia virus (BLV) is spread throughout the world and represents one of the biggest problems for the livestock production and food security in Russia. However, recent genome-wide association studies have shown that sensitivity/resistance to BLV is polygenic. The aim of this study was to create a catalog of cattle genes and genes of other mammalian species involved in the pathogenesis of BLV-induced infection and to perform gene prioritization using bioinformatics methods. Based on manually collected information from a range of open sources, a total of 446 genes were included in the catalog of cattle genes and genes of other mammals involved in the pathogenesis of BLV-induced infection. The following criteria were used to prioritize 446 genes from the catalog: (1) the gene is associated with leukemia according to a genome-wide association study; (2) the gene is associated with leukemia according to a case-control study; (3) the role of the gene in leukemia development has been studied using knockout mice; (4) protein-protein interactions exist between the gene-encoded protein and either viral particles or individual viral proteins; (5) the gene is annotated with Gene Ontology terms that are overrepresented for a given list of genes; (6) the gene participates in biological pathways from the KEGG or REACTOME databases, which are over-represented for a given list of genes; (7) the protein encoded by the gene has a high number of protein-protein interactions with proteins encoded by other genes from the catalog. Based on each criterion, a rank was assigned to each gene. Then the ranks were summarized and an overall rank was determined. Prioritization of 446 candidate genes allowed us to identify 5 genes of interest (TNF,LTB,BOLA-DQA1,BOLA-DRB3,ATF2), which can aﬀect the sensitivity/resistance of cattle to leukemia.

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Meta-analysis of genome-wide association studies for body fat distribution in 694 649 individuals of European ancestry

Human Molecular Genetics ◽

10.1093/hmg/ddy327 ◽

2018 ◽

Vol 28 (1) ◽

pp. 166-174 ◽

Cited By ~ 109

Author(s):

Sara L Pulit ◽

Charli Stoneman ◽

Andrew P Morris ◽

Andrew R Wood ◽

Craig A Glastonbury ◽

...

Keyword(s):

Body Fat ◽

Association Studies ◽

Meta Analysis ◽

Fat Distribution ◽

Body Fat Distribution ◽

Genome Wide Association ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Genome Wide ◽

A Genome

Abstract More than one in three adults worldwide is either overweight or obese. Epidemiological studies indicate that the location and distribution of excess fat, rather than general adiposity, are more informative for predicting risk of obesity sequelae, including cardiometabolic disease and cancer. We performed a genome-wide association study meta-analysis of body fat distribution, measured by waist-to-hip ratio (WHR) adjusted for body mass index (WHRadjBMI), and identified 463 signals in 346 loci. Heritability and variant effects were generally stronger in women than men, and we found approximately one-third of all signals to be sexually dimorphic. The 5% of individuals carrying the most WHRadjBMI-increasing alleles were 1.62 times more likely than the bottom 5% to have a WHR above the thresholds used for metabolic syndrome. These data, made publicly available, will inform the biology of body fat distribution and its relationship with disease.

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Genetic variations and risk of placental abruption: A genome-wide association study and meta-analysis of genome-wide association studies

Placenta ◽

10.1016/j.placenta.2018.04.008 ◽

2018 ◽

Vol 66 ◽

pp. 8-16 ◽

Cited By ~ 2

Author(s):

Tsegaselassie Workalemahu ◽

Daniel A. Enquobahrie ◽

Bizu Gelaye ◽

Sixto E. Sanchez ◽

Pedro J. Garcia ◽

...

Keyword(s):

Association Study ◽

Genome Wide Association Study ◽

Placental Abruption ◽

Association Studies ◽

Meta Analysis ◽

Genetic Variations ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genome Wide ◽

A Genome

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Genome-Wide Association for HbA1c in Malay Identified Deletion on SLC4A1 that Influences HbA1c Independent of Glycemia

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa658 ◽

2020 ◽

Vol 105 (12) ◽

pp. 3854-3864

Author(s):

Jin-Fang Chai ◽

Shih-Ling Kao ◽

Chaolong Wang ◽

Victor Jun-Yu Lim ◽

Ing Wei Khor ◽

...

Keyword(s):

Genetic Variants ◽

Hba1c Level ◽

Genome Wide Association Study ◽

Meta Analysis ◽

Genome Wide Association ◽

Specific Reference ◽

Genetic Determinants ◽

Genome Wide ◽

Whole Exome ◽

A Genome

Abstract Context Glycated hemoglobin A1c (HbA1c) level is used to screen and diagnose diabetes. Genetic determinants of HbA1c can vary across populations and many of the genetic variants influencing HbA1c level were specific to populations. Objective To discover genetic variants associated with HbA1c level in nondiabetic Malay individuals. Design and Participants We conducted a genome-wide association study (GWAS) analysis for HbA1c using 2 Malay studies, the Singapore Malay Eye Study (SiMES, N = 1721 on GWAS array) and the Living Biobank study (N = 983 on GWAS array and whole-exome sequenced). We built a Malay-specific reference panel to impute ethnic-specific variants and validate the associations with HbA1c at ethnic-specific variants. Results Meta-analysis of the 1000 Genomes imputed array data identified 4 loci at genome-wide significance (P < 5 × 10-8). Of the 4 loci, 3 (ADAM15, LINC02226, JUP) were novel for HbA1c associations. At the previously reported HbA1c locus ATXN7L3-G6PC3, association analysis using the exome data fine-mapped the HbA1c associations to a 27-bp deletion (rs769664228) at SLC4A1 that reduced HbA1c by 0.38 ± 0.06% (P = 3.5 × 10-10). Further imputation of this variant in SiMES confirmed the association with HbA1c at SLC4A1. We also showed that these genetic variants influence HbA1c level independent of glucose level. Conclusion We identified a deletion at SLC4A1 associated with HbA1c in Malay. The nonglycemic lowering of HbA1c at rs769664228 might cause individuals carrying this variant to be underdiagnosed for diabetes or prediabetes when HbA1c is used as the only diagnostic test for diabetes.

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Retrospective Association Analysis of Longitudinal Binary Traits Identifies Important Loci and Pathways in Cocaine Use

Genetics ◽

10.1534/genetics.119.302598 ◽

2019 ◽

Vol 213 (4) ◽

pp. 1225-1236 ◽

Cited By ~ 1

Author(s):

Weimiao Wu ◽

Zhong Wang ◽

Ke Xu ◽

Xinyu Zhang ◽

Amei Amei ◽

...

Keyword(s):

Association Analysis ◽

Binary Data ◽

Association Studies ◽

Association Test ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Cocaine Use ◽

Genome Wide ◽

A Genome ◽

Time Varying Covariates

Longitudinal phenotypes have been increasingly available in genome-wide association studies (GWAS) and electronic health record-based studies for identification of genetic variants that influence complex traits over time. For longitudinal binary data, there remain significant challenges in gene mapping, including misspecification of the model for phenotype distribution due to ascertainment. Here, we propose L-BRAT (Longitudinal Binary-trait Retrospective Association Test), a retrospective, generalized estimating equation-based method for genetic association analysis of longitudinal binary outcomes. We also develop RGMMAT, a retrospective, generalized linear mixed model-based association test. Both tests are retrospective score approaches in which genotypes are treated as random conditional on phenotype and covariates. They allow both static and time-varying covariates to be included in the analysis. Through simulations, we illustrated that retrospective association tests are robust to ascertainment and other types of phenotype model misspecification, and gain power over previous association methods. We applied L-BRAT and RGMMAT to a genome-wide association analysis of repeated measures of cocaine use in a longitudinal cohort. Pathway analysis implicated association with opioid signaling and axonal guidance signaling pathways. Lastly, we replicated important pathways in an independent cocaine dependence case-control GWAS. Our results illustrate that L-BRAT is able to detect important loci and pathways in a genome scan and to provide insights into genetic architecture of cocaine use.

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Genomic Variations in Susceptibility to Intracranial Aneurysm in the Korean Population

Journal of Clinical Medicine ◽

10.3390/jcm8020275 ◽

2019 ◽

Vol 8 (2) ◽

pp. 275 ◽

Cited By ~ 8

Author(s):

Eun Hong ◽

Bong Kim ◽

Steve Cho ◽

Jin Yang ◽

Hyuk Choi ◽

...

Keyword(s):

Intracranial Aneurysm ◽

Association Studies ◽

Large Population ◽

Genome Wide Association ◽

Korean Population ◽

Genome Wide Association Studies ◽

Medicine Research ◽

Genome Wide ◽

A Genome ◽

Significant Difference

Genome-wide association studies found genetic variations with modulatory effects for intracranial aneurysm (IA) formations in European and Japanese populations. We aimed to identify the susceptibility of single nucleotide polymorphisms (SNPs) to IA in a Korean population consisting of 250 patients, and 294 controls using the Asian-specific Axiom Precision Medicine Research Array. Twenty-nine SNPs reached a genome-wide significance threshold (5 × 10−8). The rs371331393 SNP, with a stop-gain function of ARHGAP32 (11q24.3), showed the most significant association with the risk of IA (OR = 43.57, 95% CI: 21.84–86.95; p = 9.3 × 10−27). Eight out of 29 SNPs—GBA (rs75822236), TCF24 (rs112859779), OLFML2A (rs79134766), ARHGAP32 (rs371331393), CD163L1 (rs138525217), CUL4A (rs74115822), LOC102724084 (rs75861150), and LRRC3 (rs116969723)—demonstrated sufficient statistical power greater than or equal to 0.8. Two previously reported SNPs, rs700651 (BOLL, 2q33.1) and rs6841581 (EDNRA, 4q31.22), were validated in our GWAS (Genome-wide association study). In a subsequent analysis, three SNPs showed a significant difference in expressions: the rs6741819 (RNF144A, 2p25.1) was down-regulated in the adrenal gland tissue (p = 1.5 × 10−6), the rs1052270 (TMOD1. 9q22.33) was up-regulated in the testis tissue (p = 8.6 × 10−10), and rs6841581 (EDNRA, 4q31.22) was up-regulated in both the esophagus (p = 5.2 × 10−12) and skin tissues (1.2 × 10−6). Our GWAS showed novel candidate genes with Korean-specific variations in IA formations. Large population based studies are thus warranted.

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A Genome-wide Association Study Identifying RAP1A as a Novel Susceptibility Gene for Crohn’s Disease in Japanese Individuals

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjy197 ◽

2018 ◽

Vol 13 (5) ◽

pp. 648-658 ◽

Cited By ~ 8

Author(s):

Yoichi Kakuta ◽

Yosuke Kawai ◽

Takeo Naito ◽

Atsushi Hirano ◽

Junji Umeno ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Mononuclear Cells ◽

Association Studies ◽

Susceptibility Gene ◽

Genome Wide Association ◽

Effector Memory ◽

Genome Wide Association Studies ◽

Genome Wide ◽

A Genome

Abstract Background and Aims Genome-wide association studies [GWASs] of European populations have identified numerous susceptibility loci for Crohn’s disease [CD]. Susceptibility genes differ by ethnicity, however, so GWASs specific for Asian populations are required. This study aimed to clarify the Japanese-specific genetic background for CD by a GWAS using the Japonica array [JPA] and subsequent imputation with the 1KJPN reference panel. Methods Two independent Japanese case/control sets (Tohoku region [379 CD patients, 1621 controls] and Kyushu region [334 CD patients, 462 controls]) were included. GWASs were performed separately for each population, followed by a meta-analysis. Two additional replication sets [254 + 516 CD patients and 287 + 565 controls] were analysed for top hit single nucleotide polymorphisms [SNPs] from novel genomic regions. Results Genotype data of 4 335 144 SNPs from 713 Japanese CD patients and 2083 controls were analysed. SNPs located in TNFSF15 (rs78898421, Pmeta = 2.59 × 10−26, odds ratio [OR] = 2.10), HLA-DQB1 [rs184950714, pmeta = 3.56 × 10−19, OR = 2.05], ZNF365, and 4p14 loci were significantly associated with CD in Japanese individuals. Replication analyses were performed for four novel candidate loci [p <1 × 10−6], and rs488200 located upstream of RAP1A was significantly associated with CD [pcombined = 4.36 × 10−8, OR = 1.31]. Transcriptome analysis of CD4+ effector memory T cells from lamina propria mononuclear cells of CD patients revealed a significant association of rs488200 with RAP1A expression. Conclusions RAP1A is a novel susceptibility locus for CD in the Japanese population.

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