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2.
Sci Rep ; 13(1): 18532, 2023 10 28.
Article in English | MEDLINE | ID: mdl-37898691

ABSTRACT

Clostridioides difficile (C. diff.) infection (CDI) is a leading cause of hospital acquired diarrhea in North America and Europe and a major cause of morbidity and mortality. Known risk factors do not fully explain CDI susceptibility, and genetic susceptibility is suggested by the fact that some patients with colons that are colonized with C. diff. do not develop any infection while others develop severe or recurrent infections. To identify common genetic variants associated with CDI, we performed a genome-wide association analysis in 19,861 participants (1349 cases; 18,512 controls) from the Electronic Medical Records and Genomics (eMERGE) Network. Using logistic regression, we found strong evidence for genetic variation in the DRB locus of the MHC (HLA) II region that predisposes individuals to CDI (P > 1.0 × 10-14; OR 1.56). Altered transcriptional regulation in the HLA region may play a role in conferring susceptibility to this opportunistic enteric pathogen.


Subject(s)
Clostridium Infections , Genome-Wide Association Study , Humans , Clostridium Infections/genetics , Diarrhea , Histocompatibility Antigens , HLA Antigens/genetics , Histocompatibility Antigens Class II , Genetic Variation
3.
J Bone Miner Res ; 30(1): 184-94, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25043339

ABSTRACT

It is important to identify the patients at highest risk of fractures. A recent large-scale meta-analysis identified 63 autosomal single-nucleotide polymorphisms (SNPs) associated with bone mineral density (BMD), of which 16 were also associated with fracture risk. Based on these findings, two genetic risk scores (GRS63 and GRS16) were developed. Our aim was to determine the clinical usefulness of these GRSs for the prediction of BMD, BMD change, and fracture risk in elderly subjects. We studied two male (Osteoporotic Fractures in Men Study [MrOS] US, MrOS Sweden) and one female (Study of Osteoporotic Fractures [SOF]) large prospective cohorts of older subjects, looking at BMD, BMD change, and radiographically and/or medically confirmed incident fractures (8067 subjects, 2185 incident nonvertebral or vertebral fractures). GRS63 was associated with BMD (≅3% of the variation explained) but not with BMD change. Both GRS63 and GRS16 were associated with fractures. After BMD adjustment, the effect sizes for these associations were substantially reduced. Similar results were found using an unweighted GRS63 and an unweighted GRS16 compared with those found using the corresponding weighted risk scores. Only minor improvements in C-statistics (AUC) for fractures were found when the GRSs were added to a base model (age, weight, and height), and no significant improvements in C-statistics were found when they were added to a model further adjusted for BMD. Net reclassification improvements with the addition of the GRSs to a base model were modest and substantially attenuated in BMD-adjusted models. GRS63 is associated with BMD, but not BMD change, suggesting that the genetic determinants of BMD differ from those of BMD change. When BMD is known, the clinical utility of the two GRSs for fracture prediction is limited in elderly subjects.


Subject(s)
Bone Density/genetics , Fractures, Bone/genetics , Models, Genetic , Osteoporosis/genetics , Polymorphism, Single Nucleotide , Aged , Aged, 80 and over , Female , Fractures, Bone/epidemiology , Humans , Male , Osteoporosis/epidemiology , Predictive Value of Tests , Prospective Studies , Risk Factors
4.
PLoS One ; 9(2): e87645, 2014.
Article in English | MEDLINE | ID: mdl-24520335

ABSTRACT

Integrating genetic data from families with highly penetrant forms of disease together with genetic data from outbred populations represents a promising strategy to uncover the complete frequency spectrum of risk alleles for complex traits such as rheumatoid arthritis (RA). Here, we demonstrate that rare, low-frequency and common alleles at one gene locus, phospholipase B1 (PLB1), might contribute to risk of RA in a 4-generation consanguineous pedigree (Middle Eastern ancestry) and also in unrelated individuals from the general population (European ancestry). Through identity-by-descent (IBD) mapping and whole-exome sequencing, we identified a non-synonymous c.2263G>C (p.G755R) mutation at the PLB1 gene on 2q23, which significantly co-segregated with RA in family members with a dominant mode of inheritance (P = 0.009). We further evaluated PLB1 variants and risk of RA using a GWAS meta-analysis of 8,875 RA cases and 29,367 controls of European ancestry. We identified significant contributions of two independent non-coding variants near PLB1 with risk of RA (rs116018341 [MAF = 0.042] and rs116541814 [MAF = 0.021], combined P = 3.2 × 10(-6)). Finally, we performed deep exon sequencing of PLB1 in 1,088 RA cases and 1,088 controls (European ancestry), and identified suggestive dispersion of rare protein-coding variant frequencies between cases and controls (P = 0.049 for C-alpha test and P = 0.055 for SKAT). Together, these data suggest that PLB1 is a candidate risk gene for RA. Future studies to characterize the full spectrum of genetic risk in the PLB1 genetic locus are warranted.


Subject(s)
Arthritis, Rheumatoid/enzymology , Arthritis, Rheumatoid/genetics , Consanguinity , Genetic Predisposition to Disease , Genome-Wide Association Study , Lysophospholipase/genetics , Base Sequence , Cohort Studies , Exome/genetics , Exons/genetics , Female , Genetic Loci/genetics , Genotyping Techniques , High-Throughput Nucleotide Sequencing , Humans , Male , Meta-Analysis as Topic , Mutation/genetics , Pedigree , Polymorphism, Single Nucleotide/genetics , Reproducibility of Results , Risk Factors , White People/genetics
5.
Nature ; 506(7488): 376-81, 2014 Feb 20.
Article in English | MEDLINE | ID: mdl-24390342

ABSTRACT

A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ∼10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2 - 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation, cis-acting expression quantitative trait loci and pathway analyses--as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes--to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.


Subject(s)
Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/genetics , Drug Discovery , Genetic Predisposition to Disease/genetics , Molecular Targeted Therapy , Alleles , Animals , Arthritis, Rheumatoid/metabolism , Arthritis, Rheumatoid/pathology , Asian People/genetics , Case-Control Studies , Computational Biology , Drug Repositioning , Female , Genome-Wide Association Study , Hematologic Neoplasms/genetics , Hematologic Neoplasms/metabolism , Humans , Male , Mice , Mice, Knockout , Polymorphism, Single Nucleotide/genetics , White People/genetics
6.
Ann Rheum Dis ; 73(6): 1170-5, 2014 Jun.
Article in English | MEDLINE | ID: mdl-23716066

ABSTRACT

OBJECTIVES: While genetic determinants of low density lipoprotein (LDL) cholesterol levels are well characterised in the general population, they are understudied in rheumatoid arthritis (RA). Our objective was to determine the association of established LDL and RA genetic alleles with LDL levels in RA cases compared with non-RA controls. METHODS: Using data from electronic medical records, we linked validated RA cases and non-RA controls to discarded blood samples. For each individual, we extracted data on: first LDL measurement, age, gender and year of LDL measurement. We genotyped subjects for 11 LDL and 44 non-HLA RA alleles, and calculated RA and LDL genetic risk scores (GRS). We tested the association between each GRS and LDL level using multivariate linear regression models adjusted for age, gender, year of LDL measurement and RA status. RESULTS: Among 567 RA cases and 979 controls, 80% were female and mean age at the first LDL measurement was 55 years. RA cases had significantly lower mean LDL levels than controls (117.2 vs 125.6 mg/dl, respectively, p<0.0001). Each unit increase in LDL GRS was associated with 0.8 mg/dl higher LDL levels in both RA cases and controls (p=3.0×10(-7)). Each unit increase in RA GRS was associated with 4.3 mg/dl lower LDL levels in both groups (p=0.01). CONCLUSIONS: LDL alleles were associated with higher LDL levels in RA. RA alleles were associated with lower LDL levels in both RA cases and controls. As RA cases carry more RA alleles, these findings suggest a genetic basis for epidemiological observations of lower LDL levels in RA.


Subject(s)
Arthritis, Rheumatoid/genetics , Dyslipidemias/genetics , Lipoproteins, LDL/blood , Adult , Aged , Arthritis, Rheumatoid/blood , Case-Control Studies , Dyslipidemias/blood , Female , Genetic Predisposition to Disease , Genotype , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide
7.
Diabetes ; 62(9): 3282-91, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23903356

ABSTRACT

Maternal metabolism during pregnancy impacts the developing fetus, affecting offspring birth weight and adiposity. This has important implications for metabolic health later in life (e.g., offspring of mothers with pre-existing or gestational diabetes mellitus have an increased risk of metabolic disorders in childhood). To identify genetic loci associated with measures of maternal metabolism obtained during an oral glucose tolerance test at ∼28 weeks' gestation, we performed a genome-wide association study of 4,437 pregnant mothers of European (n = 1,367), Thai (n = 1,178), Afro-Caribbean (n = 1,075), and Hispanic (n = 817) ancestry, along with replication of top signals in three additional European ancestry cohorts. In addition to identifying associations with genes previously implicated with measures of glucose metabolism in nonpregnant populations, we identified two novel genome-wide significant associations: 2-h plasma glucose and HKDC1, and fasting C-peptide and BACE2. These results suggest that the genetic architecture underlying glucose metabolism may differ, in part, in pregnancy.


Subject(s)
Amyloid Precursor Protein Secretases/genetics , Aspartic Acid Endopeptidases/genetics , Blood Glucose/genetics , Genome-Wide Association Study/methods , Adolescent , Adult , Amyloid Precursor Protein Secretases/physiology , Aspartic Acid Endopeptidases/physiology , C-Peptide/blood , Fasting/blood , Female , Genotype , Glucose Tolerance Test , Humans , Pregnancy , Young Adult
8.
PLoS One ; 8(6): e63481, 2013.
Article in English | MEDLINE | ID: mdl-23762230

ABSTRACT

The feasibility of using imperfectly phenotyped "silver standard" samples identified from electronic medical record diagnoses is considered in genetic association studies when these samples might be combined with an existing set of samples phenotyped with a gold standard technique. An analytic expression is derived for the power of a chi-square test of independence using either research-quality case/control samples alone, or augmented with silver standard data. The subset of the parameter space where inclusion of silver standard samples increases statistical power is identified. A case study of dementia subjects identified from electronic medical records from the Electronic Medical Records and Genomics (eMERGE) network, combined with subjects from two studies specifically targeting dementia, verifies these results.


Subject(s)
Biomarkers/metabolism , Dementia/genetics , Electronic Health Records/statistics & numerical data , Genome-Wide Association Study , Genomics , Polymorphism, Single Nucleotide/genetics , Aged , Case-Control Studies , Chi-Square Distribution , Computer Simulation , Dementia/epidemiology , Humans , Models, Statistical , Phenotype , Risk Factors
9.
Hum Mol Genet ; 22(17): 3583-96, 2013 Sep 01.
Article in English | MEDLINE | ID: mdl-23575227

ABSTRACT

Newborns characterized as large and small for gestational age are at risk for increased mortality and morbidity during the first year of life as well as for obesity and dysglycemia as children and adults. The intrauterine environment and fetal genes contribute to the fetal size at birth. To define the genetic architecture underlying the newborn size, we performed a genome-wide association study (GWAS) in 4281 newborns in four ethnic groups from the Hyperglycemia and Adverse Pregnancy Outcome Study. We tested for association with newborn anthropometric traits (birth length, head circumference, birth weight, percent fat mass and sum of skinfolds) and newborn metabolic traits (cord glucose and C-peptide) under three models. Model 1 adjusted for field center, ancestry, neonatal gender, gestational age at delivery, parity, maternal age at oral glucose tolerance test (OGTT); Model 2 adjusted for Model 1 covariates, maternal body mass index (BMI) at OGTT, maternal height at OGTT, maternal mean arterial pressure at OGTT, maternal smoking and drinking; Model 3 adjusted for Model 2 covariates, maternal glucose and C-peptide at OGTT. Strong evidence for association was observed with measures of newborn adiposity (sum of skinfolds model 3 Z-score 7.356, P = 1.90×10⁻¹³, and to a lesser degree fat mass and birth weight) and a region on Chr3q25.31 mapping between CCNL and LEKR1. These findings were replicated in an independent cohort of 2296 newborns. This region has previously been shown to be associated with birth weight in Europeans. The current study suggests that association of this locus with birth weight is secondary to an effect on fat as opposed to lean body mass.


Subject(s)
Adiposity/genetics , Birth Weight/genetics , Chromosomes, Human, Pair 3/genetics , Cyclins/genetics , Ethnicity/genetics , Proteinase Inhibitory Proteins, Secretory/genetics , Racial Groups/genetics , Asian People/genetics , Black People/genetics , Body Mass Index , Caribbean Region , Cohort Studies , Female , Genome-Wide Association Study , Humans , Infant, Newborn , Linear Models , Male , Mexican Americans/genetics , Pregnancy , Serine Peptidase Inhibitor Kazal-Type 5 , Thailand , White People/genetics
10.
Arterioscler Thromb Vasc Biol ; 33(4): 847-57, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23413431

ABSTRACT

OBJECTIVE: Low high-density lipoprotein cholesterol (HDL-C) is associated with cardiometabolic pathologies. In this study, we investigate the biological pathways and individual genes behind low HDL-C by integrating results from 3 high-throughput data sources: adipose tissue transcriptomics, HDL lipidomics, and dense marker genotypes from Finnish individuals with low or high HDL-C (n=450). APPROACH AND RESULTS: In the pathway analysis of genetic data, we demonstrate that genetic variants within inflammatory pathways were enriched among low HDL-C associated single-nucleotide polymorphisms, and the expression of these pathways upregulated in the adipose tissue of low HDL-C subjects. The lipidomic analysis highlighted the change in HDL particle quality toward putatively more inflammatory and less vasoprotective state in subjects with low HDL-C, as evidenced by their decreased antioxidative plasmalogen contents. We show that the focal point of these inflammatory pathways seems to be the HLA region with its low HDL-associated alleles also associating with more abundant local transcript levels in adipose tissue, increased plasma vascular cell adhesion molecule 1 (VCAM1) levels, and decreased HDL particle plasmalogen contents, markers of adipose tissue inflammation, vascular inflammation, and HDL antioxidative potential, respectively. In a population-based look-up of the inflammatory pathway single-nucleotide polymorphisms in a large Finnish cohorts (n=11 211), no association of the HLA region was detected for HDL-C as quantitative trait, but with extreme HDL-C phenotypes, implying the presence of low or high HDL genes in addition to the population-genomewide association studies-identified HDL genes. CONCLUSIONS: Our study highlights the role of inflammation with a genetic component in subjects with low HDL-C and identifies novel cis-expression quantitative trait loci (cis-eQTL) variants in HLA region to be associated with low HDL-C.


Subject(s)
Adipose Tissue/metabolism , Cholesterol, HDL/blood , Coronary Artery Disease/blood , Coronary Artery Disease/genetics , Gene Expression Profiling , Genomics , Inflammation/blood , Inflammation/genetics , Biomarkers/blood , Coronary Artery Disease/immunology , Female , Finland , Gene Regulatory Networks , Genetic Predisposition to Disease , Genome-Wide Association Study , HLA Antigens/genetics , Health Surveys , Humans , Inflammation/immunology , Linear Models , Logistic Models , Male , Middle Aged , Phenotype , Plasmalogens/blood , Polymorphism, Single Nucleotide , Quantitative Trait Loci , Risk Factors , Vascular Cell Adhesion Molecule-1/blood
11.
Genome Med ; 5(1): 7, 2013.
Article in English | MEDLINE | ID: mdl-23363732

ABSTRACT

Recommendations and guidance on how to handle the return of genetic results to patients have offered limited insight into how to approach incidental genetic findings in the context of clinical trials. This paper provides the Genomics and Randomized Trials Network (GARNET) recommendations on incidental genetic findings in the context of clinical trials, and discusses the ethical and practical issues considered in formulating our recommendations. There are arguments in support of as well as against returning incidental genetic findings in clinical trials. For instance, reporting incidental findings in clinical trials may improve the investigator-participant relationship and the satisfaction of participation, but it may also blur the line between clinical care and research. The issues of whether and how to return incidental genetic findings, including the costs of doing so, should be considered when developing clinical trial protocols. Once decided, plans related to sharing individual results from the aim(s) of the trial, as well as incidental findings, should be discussed explicitly in the consent form. Institutional Review Boards (IRBs) and other study-specific governing bodies should be part of the decision as to if, when, and how to return incidental findings, including when plans in this regard are being reconsidered.

12.
Hum Mol Genet ; 22(10): 2119-27, 2013 May 15.
Article in English | MEDLINE | ID: mdl-23314186

ABSTRACT

With white blood cell count emerging as an important risk factor for chronic inflammatory diseases, genetic associations of differential leukocyte types, specifically monocyte count, are providing novel candidate genes and pathways to further investigate. Circulating monocytes play a critical role in vascular diseases such as in the formation of atherosclerotic plaque. We performed a joint and ancestry-stratified genome-wide association analyses to identify variants specifically associated with monocyte count in 11 014 subjects in the electronic Medical Records and Genomics Network. In the joint and European ancestry samples, we identified novel associations in the chromosome 16 interferon regulatory factor 8 (IRF8) gene (P-value = 2.78×10(-16), ß = -0.22). Other monocyte associations include novel missense variants in the chemokine-binding protein 2 (CCBP2) gene (P-value = 1.88×10(-7), ß = 0.30) and a region of replication found in ribophorin I (RPN1) (P-value = 2.63×10(-16), ß = -0.23) on chromosome 3. The CCBP2 and RPN1 region is located near GATA binding protein2 gene that has been previously shown to be associated with coronary heart disease. On chromosome 9, we found a novel association in the prostaglandin reductase 1 gene (P-value = 2.29×10(-7), ß = 0.16), which is downstream from lysophosphatidic acid receptor 1. This region has previously been shown to be associated with monocyte count. We also replicated monocyte associations of genome-wide significance (P-value = 5.68×10(-17), ß = -0.23) at the integrin, alpha 4 gene on chromosome 2. The novel IRF8 results and further replications provide supporting evidence of genetic regions associated with monocyte count.


Subject(s)
Atherosclerosis/blood , Atherosclerosis/genetics , Chromosomes, Human/genetics , Genome-Wide Association Study , Leukocyte Count , Adult , Aged , Chromosomes, Human/metabolism , Female , GATA2 Transcription Factor/genetics , GATA2 Transcription Factor/metabolism , Humans , Integrin alpha4/genetics , Integrin alpha4/metabolism , Interferon Regulatory Factors/genetics , Interferon Regulatory Factors/metabolism , Male , Membrane Proteins/genetics , Membrane Proteins/metabolism , Middle Aged , Monocytes , Mutation, Missense , Receptors, Chemokine/genetics , Receptors, Chemokine/metabolism , Receptors, Lysophosphatidic Acid/genetics , Receptors, Lysophosphatidic Acid/metabolism
13.
Proc Natl Acad Sci U S A ; 110(2): 588-93, 2013 Jan 08.
Article in English | MEDLINE | ID: mdl-23267103

ABSTRACT

The plasma glycoprotein von Willebrand factor (VWF) exhibits fivefold antigen level variation across the normal human population determined by both genetic and environmental factors. Low levels of VWF are associated with bleeding and elevated levels with increased risk for thrombosis, myocardial infarction, and stroke. To identify additional genetic determinants of VWF antigen levels and to minimize the impact of age and illness-related environmental factors, we performed genome-wide association analysis in two young and healthy cohorts (n = 1,152 and n = 2,310) and identified signals at ABO (P < 7.9E-139) and VWF (P < 5.5E-16), consistent with previous reports. Additionally, linkage analysis based on sibling structure within the cohorts, identified significant signals at chromosome 2q12-2p13 (LOD score 5.3) and at the ABO locus on chromosome 9q34 (LOD score 2.9) that explained 19.2% and 24.5% of the variance in VWF levels, respectively. Given its strong effect, the linkage region on chromosome 2 could harbor a potentially important determinant of bleeding and thrombosis risk. The absence of a chromosome 2 association signal in this or previous association studies suggests a causative gene harboring many genetic variants that are individually rare, but in aggregate common. These results raise the possibility that similar loci could explain a significant portion of the "missing heritability" for other complex genetic traits.


Subject(s)
Chromosomes, Human, Pair 2/genetics , Chromosomes, Human, Pair 9/genetics , Genetic Linkage/genetics , Quantitative Trait Loci/genetics , von Willebrand Factor/genetics , ABO Blood-Group System/genetics , Adolescent , Adult , Age Factors , Computational Biology , Gene Frequency , Genome-Wide Association Study , Genotype , Haplotypes/genetics , Humans , Lod Score , Polymorphism, Single Nucleotide/genetics , Principal Component Analysis , Sex Factors , von Willebrand Factor/metabolism
14.
PLoS Genet ; 8(9): e1002921, 2012 Sep.
Article in English | MEDLINE | ID: mdl-23028342

ABSTRACT

Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ~2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2 × 10(-8)) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0 × 10(-9)). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-ß1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1 × 10(-7)), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.


Subject(s)
Diabetes Mellitus, Type 1/genetics , Diabetic Nephropathies/genetics , ErbB Receptors/genetics , Kidney Failure, Chronic , Nuclear Proteins/genetics , Diabetes Mellitus, Type 1/complications , Diabetic Nephropathies/etiology , Diabetic Nephropathies/pathology , Fibrosis/genetics , Fibrosis/metabolism , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Kidney Failure, Chronic/etiology , Kidney Failure, Chronic/genetics , Kidney Failure, Chronic/pathology , Kidney Tubules/metabolism , Kidney Tubules/pathology , Polymorphism, Single Nucleotide , Quantitative Trait Loci/genetics , Receptor, ErbB-4 , Transforming Growth Factor beta1/genetics , Transforming Growth Factor beta1/metabolism
15.
Cancer Epidemiol Biomarkers Prev ; 21(11): 2048-58, 2012 Nov.
Article in English | MEDLINE | ID: mdl-22923026

ABSTRACT

BACKGROUND: There have been few genome-wide association studies (GWAS) of prostate cancer among diverse populations. To search for novel prostate cancer risk variants, we conducted GWAS of prostate cancer in Japanese and Latinos. In addition, we tested prostate cancer risk variants and developed genetic risk models of prostate cancer for Japanese and Latinos. METHODS: Our first-stage GWAS of prostate cancer included Japanese (cases/controls = 1,033/1,042) and Latino (cases/controls = 1,043/1,057) from the Multiethnic Cohort (MEC). Significant associations from stage I (P < 1.0 × 10(-4)) were examined in silico in GWAS of prostate cancer (stage II) in Japanese (cases/controls = 1,583/3,386) and Europeans (cases/controls = 1,854/1,894). RESULTS: No novel stage I single-nucleotide polymorphism (SNP) outside of known risk regions reached genome-wide significance. For Japanese, in stage I, the most notable putative novel association was seen with 10 SNPs (P ≤ 8.0 × 10(-6)) at chromosome 2q33; however, this was not replicated in stage II. For Latinos, the most significant association was observed with rs17023900 at the known 3p12 risk locus (stage I: OR = 1.45; P = 7.01 × 10(-5) and stage II: OR = 1.58; P = 3.05 × 10(-7)). The majority of the established risk variants for prostate cancer, 79% and 88%, were positively associated with prostate cancer in Japanese and Latinos (stage I), respectively. The cumulative effects of these variants significantly influence prostate cancer risk (OR per allele = 1.10; P = 2.71 × 10(-25) and OR = 1.07; P = 1.02 × 10(-16) for Japanese and Latinos, respectively). CONCLUSION AND IMPACT: Our GWAS of prostate cancer did not identify novel genome-wide significant variants. However, our findings show that established risk variants for prostate cancer significantly contribute to risk among Japanese and Latinos.


Subject(s)
Asian People/genetics , Hispanic or Latino/genetics , Prostatic Neoplasms/ethnology , Prostatic Neoplasms/genetics , California/epidemiology , Cohort Studies , Genetic Predisposition to Disease , Genome-Wide Association Study , Genotype , Hawaii/epidemiology , Humans , Japan/ethnology , Male , Models, Statistical , Neoplasm Staging , Polymorphism, Single Nucleotide , Prostatic Neoplasms/epidemiology , Prostatic Neoplasms/pathology , Risk , SEER Program
17.
PLoS Genet ; 8(4): e1002654, 2012.
Article in English | MEDLINE | ID: mdl-22570617

ABSTRACT

Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63-0.75], p = 1.86×10⁻¹8), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21-1.43], p = 3.87×10⁻¹¹). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50-0.67], p = 1.17×10⁻¹²) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53-0.72], p = 8.88×10⁻¹°). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41-0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54-1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma.


Subject(s)
Exfoliation Syndrome/genetics , Genome-Wide Association Study , Glaucoma, Open-Angle/genetics , Nerve Degeneration , Transforming Growth Factor beta , Alleles , Chromosomes, Human, Pair 8 , Chromosomes, Human, Pair 9 , Homeodomain Proteins/genetics , Humans , Nerve Degeneration/genetics , Nerve Degeneration/pathology , Optic Nerve/pathology , Polymorphism, Single Nucleotide , RNA, Long Noncoding , RNA, Untranslated/genetics , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta/metabolism
18.
Genet Med ; 14(4): 424-31, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22361898

ABSTRACT

PURPOSE: Return of individual genetic results to research participants, including participants in archives and biorepositories, is receiving increased attention. However, few groups have deliberated on specific results or weighed deliberations against relevant local contextual factors. METHODS: The Electronic Medical Records and Genomics (eMERGE) Network, which includes five biorepositories conducting genome-wide association studies, convened a return of results oversight committee to identify potentially returnable results. Network-wide deliberations were then brought to local constituencies for final decision making. RESULTS: Defining results that should be considered for return required input from clinicians with relevant expertise and much deliberation. The return of results oversight committee identified two sex chromosomal anomalies, Klinefelter syndrome and Turner syndrome, as well as homozygosity for factor V Leiden, as findings that could warrant reporting. Views about returning findings of HFE gene mutations associated with hemochromatosis were mixed due to low penetrance. Review of electronic medical records suggested that most participants with detected abnormalities were unaware of these findings. Local considerations relevant to return varied and, to date, four sites have elected not to return findings (return was not possible at one site). CONCLUSION: The eMERGE experience reveals the complexity of return of results decision making and provides a potential deliberative model for adoption in other collaborative contexts.


Subject(s)
Biomedical Research/statistics & numerical data , Genome-Wide Association Study/statistics & numerical data , Research Subjects , Biomedical Research/ethics , Factor V/genetics , Genetics, Medical/ethics , Genetics, Medical/statistics & numerical data , Genome-Wide Association Study/ethics , Homozygote , Humans , Incidental Findings , Klinefelter Syndrome/diagnosis , Klinefelter Syndrome/genetics , Medical Informatics/ethics , Medical Informatics/statistics & numerical data , Sex Chromosome Aberrations , Truth Disclosure/ethics , Turner Syndrome/diagnosis , Turner Syndrome/genetics
19.
Hum Genet ; 131(4): 639-52, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22037903

ABSTRACT

White blood cell count (WBC) is unique among identified inflammatory predictors of chronic disease in that it is routinely measured in asymptomatic patients in the course of routine patient care. We led a genome-wide association analysis to identify variants associated with WBC levels in 13,923 subjects in the electronic Medical Records and Genomics (eMERGE) Network. We identified two regions of interest that were each unique to subjects of genetically determined ancestry to the African continent (AA) or to the European continent (EA). WBC varies among different ancestry groups. Despite being ancestry specific, these regions were identifiable in the combined analysis. In AA subjects, the region surrounding the Duffy antigen/chemokine receptor gene (DARC) on 1q21 exhibited significant association (p value = 6.71e-55). These results validate the previously reported association between WBC and of the regulatory variant rs2814778 in the promoter region, which causes the Duffy negative phenotype (Fy-/-). A second missense variant (rs12075) is responsible for the two principal antigens, Fya and Fyb of the Duffy blood group system. The two variants, consisting of four alleles, act in concert to produce five antigens and subsequent phenotypes. We were able to identify the marginal and novel interaction effects of these two variants on WBC. In the EA subjects, we identified significantly associated SNPs tagging three separate genes in the 17q21 region: (1) GSDMA, (2) MED24, and (3) PSMD3. Variants in this region have been reported to be associated with WBC, neutrophil count, and inflammatory diseases including asthma and Crohn's disease.


Subject(s)
Genetic Variation , Genome-Wide Association Study/methods , Leukocyte Count , Adult , Aged , Aged, 80 and over , Alleles , Black People/genetics , Duffy Blood-Group System/genetics , Female , Gene Frequency , Genome, Human/genetics , Genome-Wide Association Study/statistics & numerical data , Genotype , Humans , Male , Mediator Complex/genetics , Medical Records/statistics & numerical data , Middle Aged , Neoplasm Proteins/genetics , Polymorphism, Single Nucleotide , Principal Component Analysis , Proteasome Endopeptidase Complex/genetics , Receptors, Cell Surface/genetics , White People/genetics , White People/statistics & numerical data
20.
Stand Genomic Sci ; 5(2): 224-9, 2011 Nov 30.
Article in English | MEDLINE | ID: mdl-22180825

ABSTRACT

Genotyping experiments are widely used in clinical and basic research laboratories to identify associations between genetic variations and normal/abnormal phenotypes. Genotyping assay techniques vary from single genomic regions that are interrogated using PCR reactions to high throughput assays examining genome-wide sequence and structural variation. The resulting genotype data may include millions of markers of thousands of individuals, requiring various statistical, modeling or other data analysis methodologies to interpret the results. To date, there are no standards for reporting genotyping experiments. Here we present the Minimum Information about a Genotyping Experiment (MIGen) standard, defining the minimum information required for reporting genotyping experiments. MIGen standard covers experimental design, subject description, genotyping procedure, quality control and data analysis. MIGen is a registered project under MIBBI (Minimum Information for Biological and Biomedical Investigations) and is being developed by an interdisciplinary group of experts in basic biomedical science, clinical science, biostatistics and bioinformatics. To accommodate the wide variety of techniques and methodologies applied in current and future genotyping experiment, MIGen leverages foundational concepts from the Ontology for Biomedical Investigations (OBI) for the description of the various types of planned processes and implements a hierarchical document structure. The adoption of MIGen by the research community will facilitate consistent genotyping data interpretation and independent data validation. MIGen can also serve as a framework for the development of data models for capturing and storing genotyping results and experiment metadata in a structured way, to facilitate the exchange of metadata.

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