scholarly journals Genetic modifiers of menopausal hormone replacement therapy and breast cancer risk: a genome–wide interaction study

2013 ◽  
Vol 20 (6) ◽  
pp. 875-887 ◽  
Author(s):  
Anja Rudolph ◽  
Rebecca Hein ◽  
Sara Lindström ◽  
Lars Beckmann ◽  
Sabine Behrens ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fixed Effects ◽  
Association Studies ◽  
Meta Analysis ◽  
Case Control ◽  
Genome Wide Association Studies ◽  
Genetic Modifiers ◽  
Genome Wide ◽  
A Genome ◽  
Increased Risk

Women using menopausal hormone therapy (MHT) are at increased risk of developing breast cancer (BC). To detect genetic modifiers of the association between current use of MHT and BC risk, we conducted a meta-analysis of four genome-wide case-only studies followed by replication in 11 case–control studies. We used a case-only design to assess interactions between single-nucleotide polymorphisms (SNPs) and current MHT use on risk of overall and lobular BC. The discovery stage included 2920 cases (541 lobular) from four genome-wide association studies. The top 1391 SNPs showing P values for interaction (Pint) <3.0×10−3 were selected for replication using pooled case–control data from 11 studies of the Breast Cancer Association Consortium, including 7689 cases (676 lobular) and 9266 controls. Fixed-effects meta-analysis was used to derive combined Pint. No SNP reached genome-wide significance in either the discovery or combined stage. We observed effect modification of current MHT use on overall BC risk by two SNPs on chr13 near POMP (combined Pint≤8.9×10−6), two SNPs in SLC25A21 (combined Pint≤4.8×10−5), and three SNPs in PLCG2 (combined Pint≤4.5×10−5). The association between lobular BC risk was potentially modified by one SNP in TMEFF2 (combined Pint≤2.7×10−5), one SNP in CD80 (combined Pint≤8.2×10−6), three SNPs on chr17 near TMEM132E (combined Pint≤2.2×10−6), and two SNPs on chr18 near SLC25A52 (combined Pint≤4.6×10−5). In conclusion, polymorphisms in genes related to solute transportation in mitochondria, transmembrane signaling, and immune cell activation are potentially modifying BC risk associated with current use of MHT. These findings warrant replication in independent studies.

scholarly journals Variants Close to NTRK2 Gene Are Associated With Birth Weight in Female Twins

2014 ◽  
Vol 17 (4) ◽  
pp. 254-261 ◽  
Author(s):  
Sarah J. Metrustry ◽  
Mark H. Edwards ◽  
Sarah E. Medland ◽  
John W. Holloway ◽  
Grant W. Montgomery ◽  
...  
Keyword(s):  
Birth Weight ◽  
Fixed Effects ◽  
Association Studies ◽  
Meta Analysis ◽  
Chromosome 9 ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
A Genome ◽  
Singleton Birth ◽  
The Difference

Low weight at birth has previously been shown to be associated with a number of adult diseases such as type 2 diabetes, cardiovascular disease, high blood pressure, and obesity later in life. Genome-wide association studies (GWAS) have been published for singleton-born individuals, but the role of genetic variation in birth weight (BW) in twins has not yet been fully investigated. A GWAS was performed in 4,593 female study participants with BW data available from the TwinsUK cohort. A genome-wide significant signal was found in chromosome 9, close to the NTRK2 gene (OMIM: 600456). QIMR, an Australian twin cohort (n = 3,003), and UK-based singleton-birth individuals from the Hertfordshire cohort (n = 2,997) were used as replication for the top two single nucleotide polymorphism (SNPs) underpinning this signal, rs12340987 and rs7849941. The top SNP, rs12340987, was found to be in the same direction in the Australian twins and in the singleton-born females (fixed effects meta-analysis beta = -0.13, SE = 0.02, and p = 1.48 × 10−8) but not in the singleton-born males tested. These findings provide an important insight into the genetic component of BW in twins who are normally excluded due to their lower BW when compared with singleton births, as well as the difference in BW between twins. The NTRK2 gene identified in this study has previously been associated with obesity.

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

2018 ◽  
Vol 28 (1) ◽  
pp. 166-174 ◽  
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.

scholarly journals A Review of the Hereditary Component of Triple Negative Breast Cancer: High- and Moderate-Penetrance Breast Cancer Genes, Low-Penetrance Loci, and the Role of Nontraditional Genetic Elements

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Darrell L. Ellsworth ◽  
Clesson E. Turner ◽  
Rachel E. Ellsworth
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Large Scale ◽  
Triple Negative ◽  
Association Studies ◽  
African Ancestry ◽  
Genome Wide Association Studies ◽  
Genetic Elements ◽  
Genome Wide ◽  
Increased Risk

Triple negative breast cancer (TNBC), representing 10-15% of breast tumors diagnosed each year, is a clinically defined subtype of breast cancer associated with poor prognosis. The higher incidence of TNBC in certain populations such as young women and/or women of African ancestry and a unique pathological phenotype shared between TNBC and BRCA1-deficient tumors suggest that TNBC may be inherited through germline mutations. In this article, we describe genes and genetic elements, beyond BRCA1 and BRCA2, which have been associated with increased risk of TNBC. Multigene panel testing has identified high- and moderate-penetrance cancer predisposition genes associated with increased risk for TNBC. Development of large-scale genome-wide SNP assays coupled with genome-wide association studies (GWAS) has led to the discovery of low-penetrance TNBC-associated loci. Next-generation sequencing has identified variants in noncoding RNAs, viral integration sites, and genes in underexplored regions of the human genome that may contribute to the genetic underpinnings of TNBC. Advances in our understanding of the genetics of TNBC are driving improvements in risk assessment and patient management.

scholarly journals Genetic Determinants of Antibody-Mediated Immune Responses to Infectious Diseases Agents: A Genome-Wide and HLA Association Study

2020 ◽  
Vol 7 (11) ◽  
Author(s):  
Guillaume Butler-Laporte ◽  
Devin Kreuzer ◽  
Tomoko Nakanishi ◽  
Adil Harroud ◽  
Vincenzo Forgetta ◽  
...  
Keyword(s):  
Infectious Diseases ◽  
Immune Responses ◽  
Vaccine Development ◽  
Association Studies ◽  
Case Control ◽  
Genome Wide Association Studies ◽  
Genetic Determinants ◽  
Hla Association ◽  
Genome Wide ◽  
A Genome

Abstract Background Infectious diseases are causally related to a large array of noncommunicable diseases (NCDs). Identifying genetic determinants of infections and antibody-mediated immune responses may shed light on this relationship and provide therapeutic targets for drug and vaccine development. Methods We used the UK biobank cohort of up to 10 000 serological measurements of infectious diseases and genome-wide genotyping. We used data on 13 pathogens to define 46 phenotypes: 15 seropositivity case–control phenotypes and 31 quantitative antibody measurement phenotypes. For each of these, we performed genome-wide association studies (GWAS) using the fastGWA linear mixed model package and human leukocyte antigen (HLA) classical allele and amino acid residue associations analyses using Lasso regression for variable selection. Results We included a total of 8735 individuals for case–control phenotypes, and an average (range) of 4286 (276–8555) samples per quantitative analysis. Fourteen of the GWAS yielded a genome-wide significant (P &lt; 5 ×10-8) locus at the major histocompatibility complex (MHC) on chromosome 6. Outside the MHC, we found a total of 60 loci, multiple associated with Epstein-Barr virus (EBV)–related NCDs (eg, RASA3, MED12L, and IRF4). FUT2 was also identified as an important gene for polyomaviridae. HLA analysis highlighted the importance of DRB1*09:01, DQB1*02:01, DQA1*01:02, and DQA1*03:01 in EBV serologies and of DRB1*15:01 in polyomaviridae. Conclusions We have identified multiple genetic variants associated with antibody immune response to 13 infections, many of which are biologically plausible therapeutic or vaccine targets. This may help prioritize future research and drug development.

Abstract 050: Meta-analysis of Genetic Associations in up to 339,224 Individuals Identify 66 New Loci for Bmi, Confirming a Neuronal Contribution to Body Weight Regulation and Implicating Several Novel Pathways

Circulation ◽  
2013 ◽  
Vol 127 (suppl_12) ◽  
Author(s):  
Anne Justice ◽  
Kari North ◽  
Ruth Loos ◽  
Sailaja Vedantam ◽  
Felix Day ◽  
...  
Keyword(s):  
Risk Factors ◽  
Fixed Effects ◽  
Association Studies ◽  
Meta Analysis ◽  
European Ancestry ◽  
Specific Gene ◽  
Genome Wide Association Studies ◽  
Cvd Risk Factors ◽  
Cvd Risk ◽  
Genome Wide

Obesity is a rising global concern as it substantially contributes to cardiovascular disease (CVD) and CVD risk factors (e.g. insulin resistance, dyslipidemia, Type 2 Diabetes). BMI (body mass index) is an easily obtained measure of obesity, which is highly heritable, and often used as a proxy when searching for genetic risk factors. Previous analyses of genome-wide association studies (GWAS) in the GIANT (Genetic Investigation of ANthropometric Traits) Consortium identified 32 loci containing common variants associated with BMI in adults of European ancestry. To enhance discovery of common causal variants for BMI, GIANT has expanded to include 82 studies with GWAS data and 43 studies with Metabochip data in more ancestrally diverse populations including up to 339,224 individuals. We performed a meta-analysis of the study-specific summary statistics for the BMI associations, assuming an additive model and using a fixed-effects inverse variance method. SNPs in 97 loci reached genome-wide significance (P<10-8), of which 31 loci had previously been identified for BMI in European-descent samples. Of the 66 novel BMI loci, three had previously been identified for association with adiposity related traits in specific populations. Many of the 97 loci contain strong biological candidates, and multiple methods were employed to pinpoint the most likely candidate gene(s) within the main signal regions. In addition to manual curation, GRAIL, and MAGENTA, we also employed a newly developed, unbiased computational approach that integrates a variety of data types (i.e. tissue-specific gene expression data, phenotypic information from mouse knockout studies, etc.) to identify potentially causal genes and pathways. Consistent with previous findings, many of these BMI loci contain genes that have a potential neuronal role in regulating appetite (e.g. MC4R, POMC, GRID1, NAV1 ). Our analyses also highlight loci with genes in pathways that were previously less apparent, such as those related to glucose and insulin homeostasis ( TCF7L2 , GIPR ), lipid metabolism ( APOE -cluster, NPC1 , NR1H3 ), the immune system ( TLR4) , and others. Additionally, many of the newly associated variants are in high LD with previously identified SNPs associated with related phenotypes, including other CVD risk factors (e.g. SNPs nearby IRS1 associated with T2D, adiposity, HDL, TG, adiponectin levels, and CHD; and SNPs near NT5C2 associated with CHD and blood pressure variables). This large-scale meta-analysis has greatly increased the number of identified obesity-susceptibility loci and continues to contribute to our understanding of the complex biology of adiposity. Our results have highlighted overlapping GWAS signals and important pathways which connect BMI and other CVD risk factors supporting the importance of pleiotropic effects in the pathogenesis of common complex diseases.

scholarly journals A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11

2012 ◽  
Vol 21 (24) ◽  
pp. 5373-5384 ◽  
Author(s):  
Afshan Siddiq ◽  
Fergus J. Couch ◽  
Gary K. Chen ◽  
Sara Lindström ◽  
Diana Eccles ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Association Studies ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Susceptibility Loci ◽  
Genome Wide

scholarly journals Technical Note: Efficient and accurate estimation of genotype odds ratios in biobank-based unbalanced case-control studies

2019 ◽  
Author(s):  
Rounak Dey ◽  
Seunggeun Lee
Keyword(s):  
Large Scale ◽  
Association Studies ◽  
Case Control ◽  
Accurate Estimation ◽  
Genome Wide Association Studies ◽  
Odds Ratios ◽  
Case Control Studies ◽  
Genome Wide ◽  
A Genome ◽  
Wide Scale

AbstractIn genome-wide association studies (GWASs), genotype log-odds ratios (LORs) quantify the effects of the variants on the binary phenotypes, and calculating the genotype LORs for all of the markers is required for several downstream analyses. Calculating genotype LORs at a genome-wide scale is computationally challenging, especially when analyzing large-scale biobank data, which involves performing thousands of GWASs phenome-wide. Since most of the binary phenotypes in biobank-based studies have unbalanced (case : control = 1 : 10) or often extremely unbalanced (case : control = 1 : 100) case-control ratios, the existing methods cannot provide a scalable and accurate way to estimate the genotype LORs. The traditional logistic regression provides biased LOR estimates in such situations. Although the Firth bias correction method can provide unbiased LOR estimates, it is not scalable for genome-wide or phenome-wide scale association analyses typically used in biobank-based studies, especially when the number of non-genetic covariates is large. On the other hand, the saddlepoint approximation-based test (fastSPA), which can provide accurate p values and is scalable to analyse large-scale biobank data, does not provide the genotype LOR estimates as it is a score-based test. Here, we propose a scalable method based on score statistics, to accurately estimate the genotype LORs, adjusting for non-genetic covariates. Comparing to the Firth method, our proposed method reduces the computational complexity from O(nK2 + K3) to O(n), where n is the sample-size, and K is the number of non-genetic covariates. Our method is ~ 10x faster than the Firth method when 15 covariates are being adjusted for. Through extensive numerical simulations, we show that the proposed method is both scalable and accurate in estimating the genotype ORs in genome-wide or phenome-wide scale.

scholarly journals Ethnic and trans-ethnic genome-wide association studies identify new loci influencing Japanese Alzheimer’s disease risk

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Daichi Shigemizu ◽  
Risa Mitsumori ◽  
Shintaro Akiyama ◽  
Akinori Miyashita ◽  
Takashi Morizono ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Japanese Population ◽  
Disease Risk ◽  
Association Studies ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
A Genome

AbstractAlzheimer’s disease (AD) has no cure, but early detection and risk prediction could allow earlier intervention. Genetic risk factors may differ between ethnic populations. To discover novel susceptibility loci of AD in the Japanese population, we conducted a genome-wide association study (GWAS) with 3962 AD cases and 4074 controls. Out of 4,852,957 genetic markers that passed stringent quality control filters, 134 in nine loci, including APOE and SORL1, were convincingly associated with AD. Lead SNPs located in seven novel loci were genotyped in an independent Japanese AD case–control cohort. The novel locus FAM47E reached genome-wide significance in a meta-analysis of association results. This is the first report associating the FAM47E locus with AD in the Japanese population. A trans-ethnic meta-analysis combining the results of the Japanese data sets with summary statistics from stage 1 data of the International Genomics of Alzheimer’s Project identified an additional novel susceptibility locus in OR2B2. Our data highlight the importance of performing GWAS in non-European populations.

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