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      Sex-specific glioma genome-wide association study identifies new risk locus at 3p21.31 in females, and finds sex-differences in risk at 8q24.21

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      1 , 2 , 3 , 4 , 5 , 6 , 1 , 5 , 2 , 5 , 5 , 5 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 8 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 29 , 30 , 29 , 29 , 30 , 29 , 30 , GliomaScan consortium, 4 , 31 , 28 , 1 , 2 ,
      Scientific Reports
      Nature Publishing Group UK

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          Abstract

          Incidence of glioma is approximately 50% higher in males. Previous analyses have examined exposures related to sex hormones in women as potential protective factors for these tumors, with inconsistent results. Previous glioma genome-wide association studies (GWAS) have not stratified by sex. Potential sex-specific genetic effects were assessed in autosomal SNPs and sex chromosome variants for all glioma, GBM and non-GBM patients using data from four previous glioma GWAS. Datasets were analyzed using sex-stratified logistic regression models and combined using meta-analysis. There were 4,831 male cases, 5,216 male controls, 3,206 female cases and 5,470 female controls. A significant association was detected at rs11979158 (7p11.2) in males only. Association at rs55705857 (8q24.21) was stronger in females than in males. A large region on 3p21.31 was identified with significant association in females only. The identified differences in effect of risk variants do not fully explain the observed incidence difference in glioma by sex.

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          USING THE CORRECT STATISTICAL TEST FOR THE EQUALITY OF REGRESSION COEFFICIENTS

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            A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer.

            We conducted a genome-wide association study (GWAS) of breast cancer by genotyping 528,173 SNPs in 1,145 postmenopausal women of European ancestry with invasive breast cancer and 1,142 controls. We identified four SNPs in intron 2 of FGFR2 (which encodes a receptor tyrosine kinase and is amplified or overexpressed in some breast cancers) that were highly associated with breast cancer and confirmed this association in 1,776 affected individuals and 2,072 controls from three additional studies. Across the four studies, the association with all four SNPs was highly statistically significant (P(trend) for the most strongly associated SNP (rs1219648) = 1.1 x 10(-10); population attributable risk = 16%). Four SNPs at other loci most strongly associated with breast cancer in the initial GWAS were not associated in the replication studies. Our summary results from the GWAS are available online in a form that should speed the identification of additional risk loci.
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              ALSPAC--the Avon Longitudinal Study of Parents and Children. I. Study methodology.

              ALSPAC (The Avon Longitudinal Study of Parents and Children, formerly the Avon Longitudinal Study of Pregnancy and Childhood) was specifically designed to determine ways in which the individual's genotype combines with environmental pressures to influence health and development. To date, there are comprehensive data on approximately 10,000 children and their parents, from early pregnancy until the children are aged between 8 and 9. The study aims to continue to collect detailed data on the children as they go through puberty noting, in particular, changes in anthropometry, attitudes and behaviour, fitness and other cardiovascular risk factors, bone mineralisation, allergic symptoms and mental health. The study started early during pregnancy and collected very detailed data from the mother and her partner before the child was born. This not only provided accurate data on concurrent features, especially medication, symptoms, diet and lifestyle, attitudes and behaviour, social and environmental features, but was unbiased by parental knowledge of any problems that the child might develop. From the time of the child's birth many different aspects of the child's environment have been monitored and a wide range of phenotypic data collected. By virtue of being based in one geographic area, linkage to medical and educational records is relatively simple, and hands-on assessments of children and parents using local facilities has the advantage of high quality control. The comprehensiveness of the ALSPAC approach with a total population sample unselected by disease status, and the availability of parental genotypes, provides an adequate sample for statistical analysis and for avoiding spurious results. The study has an open policy in regard to collaboration within strict confidentiality rules.
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                Author and article information

                Contributors
                jsb42@case.edu
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                9 May 2018
                9 May 2018
                2018
                : 8
                : 7352
                Affiliations
                [1 ]ISNI 0000 0001 2160 926X, GRID grid.39382.33, Department of Medicine, Section of Epidemiology and Population Sciences, Dan L. Duncan Comprehensive Cancer Center, , Baylor College of Medicine, ; Houston, Texas United States of America
                [2 ]ISNI 0000 0001 2164 3847, GRID grid.67105.35, Case Comprehensive Cancer Center, , Case Western Reserve University School of Medicine, Cleveland, ; Ohio, United States of America
                [3 ]ISNI 0000 0001 2164 3847, GRID grid.67105.35, Department of Population and Quantitative Heath Sciences, , Case Western Reserve University School of Medicine, Cleveland, ; Ohio, United States of America
                [4 ]ISNI 0000 0001 1271 4623, GRID grid.18886.3f, Division of Genetics and Epidemiology, , The Institute of Cancer Research, Sutton, ; Surrey, United Kingdom
                [5 ]Department of Neurological Surgery and Institute of Human Genetics, School of Medicine, University of California, San Francisco, San Francisco, California, United States of America
                [6 ]ISNI 0000 0004 0459 167X, GRID grid.66875.3a, Division of Biomedical Statistics and Informatics, , Mayo Clinic College of Medicine, ; Rochester, Minnesota United States of America
                [7 ]ISNI 0000 0001 2160 926X, GRID grid.39382.33, Institute for Clinical and Translational Research, Dan L. Duncan Comprehensive Cancer Center, , Baylor College of Medicine, ; Houston, Texas United States of America
                [8 ]ISNI 0000 0001 2171 9952, GRID grid.51462.34, Department of Epidemiology and Biostatistics, , Memorial Sloan Kettering Cancer Center, New York, ; New York, United States of America
                [9 ]ISNI 0000000419368710, GRID grid.47100.32, School of Public Health, , Yale University, ; New Haven, Connecticut United States of America
                [10 ]ISNI 0000 0004 0378 8294, GRID grid.62560.37, Department of Neurosurgery, , Brigham and Women’s Hospital, Boston, ; Massachusetts, United States of America
                [11 ]ISNI 0000 0004 1936 7400, GRID grid.256304.6, Department of Epidemiology and Biostatistics, School of Public Health, , Georgia State University, ; Atlanta, Georgia United States of America
                [12 ]ISNI 0000000100241216, GRID grid.189509.c, Cancer Control and Prevention Program, Department of Community and Family Medicine, , Duke University Medical Center, ; Durham, North Carolina United States of America
                [13 ]ISNI 0000 0004 1936 7961, GRID grid.26009.3d, Duke Cancer Institute, Duke University Medical Center, ; Durham, North Carolina United States of America
                [14 ]GRID grid.475435.4, Oncology clinic, , Finsen Center, Rigshospitalet, ; Copenhagen, Denmark
                [15 ]ISNI 0000 0001 2175 6024, GRID grid.417390.8, Survivorship Research Unit, , The Danish Cancer Society Research Center, ; Copenhagen, Denmark
                [16 ]ISNI 0000 0004 0459 167X, GRID grid.66875.3a, Department of Neurology, , Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, ; Rochester, Minnesota United States of America
                [17 ]ISNI 0000 0001 2156 6853, GRID grid.42505.36, Department of Neurology, Keck School of Medicine, , University of Southern California, Los Angeles, ; California, United States of America
                [18 ]ISNI 0000 0001 2156 6853, GRID grid.42505.36, Department of Preventive Medicine, Keck School of Medicine, , University of Southern California, Los Angeles, ; California, United States of America
                [19 ]ISNI 0000 0004 0400 4439, GRID grid.240372.0, Department of Neurology, , NorthShore University HealthSystem, ; Evanston, Illinois United States of America
                [20 ]ISNI 0000 0001 2107 2845, GRID grid.413795.d, Cancer and Radiation Epidemiology Unit, , Gertner Institute, Chaim Sheba Medical Center, ; Tel Hashomer, Israel
                [21 ]ISNI 0000 0004 1937 0546, GRID grid.12136.37, Department of Epidemiology and Preventive Medicine, School of Public Health, , Sackler Faculty of Medicine, Tel-Aviv University, ; Tel-Aviv, Israel
                [22 ]ISNI 0000 0000 9136 933X, GRID grid.27755.32, Department of Public Health Sciences, , University of Virginia School of Medicine, ; Charlottesville, Virginia United States of America
                [23 ]ISNI 0000 0001 2291 4776, GRID grid.240145.6, Department of Biostatistics, , University of Texas MD Anderson Cancer Center, ; Houston, Texas United States of America
                [24 ]ISNI 0000 0001 2355 7002, GRID grid.4367.6, Department of Pediatrics, , Washington University School of Medicine, ; St. Louis, Missouri United States of America
                [25 ]ISNI 0000 0001 2355 7002, GRID grid.4367.6, Department of Neuroscience, , Washington University School of Medicine, ; St. Louis, Missouri United States of America
                [26 ]ISNI 0000 0001 0675 4725, GRID grid.239578.2, Department of Stem Cell Biology and Regenerative Medicine, , Cleveland Clinic Foundation, Cleveland, ; Ohio, United States of America
                [27 ]ISNI 0000 0004 0507 3225, GRID grid.250942.8, Cancer and Cell Biology Division, , The Translational Genomics Research Institute, ; Phoenix, Arizona United States of America
                [28 ]ISNI 0000 0001 1034 3451, GRID grid.12650.30, Department of Radiation Sciences, , Faculty of Medicine, Umeå University, ; Umeå, Sweden
                [29 ]ISNI 0000 0004 1936 8075, GRID grid.48336.3a, Division of Cancer Epidemiology and Genetics, , National Cancer Institute, ; Rockville, Maryland United States of America
                [30 ]ISNI 0000 0004 4665 8158, GRID grid.419407.f, Core Genotyping Facility, National Cancer Institute, , SAIC-Frederick, Inc, ; Gaithersburg, Maryland United States of America
                [31 ]ISNI 0000 0004 0459 167X, GRID grid.66875.3a, Department of Laboratory Medicine and Pathology, , Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, ; Rochester, Minnesota United States of America
                [32 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Department of Epidemiology, , John Hopkins Bloomberg School of Public Health, ; Baltimore, Maryland United States of America
                [33 ]ISNI 0000 0004 0371 6485, GRID grid.422418.9, American Cancer Society, ; Atlanta, Georgia United States of America
                [34 ]ISNI 0000 0000 9241 5705, GRID grid.24381.3c, Department of Oncology, , Karolinska University Hospital, ; Stockholm, Sweden
                [35 ]ISNI 0000 0004 1936 7531, GRID grid.429997.8, Department of Public Health and Community Medicine, , Tufts University School of Medicine, Boston, ; Massachusetts, United States of America
                [36 ]ISNI 0000 0004 1937 0626, GRID grid.4714.6, Institute of Environmental Medicine, Karolinska Institutet, ; Stockholm, Sweden
                [37 ]ISNI 0000 0001 1482 3639, GRID grid.3263.4, Cancer Epidemiology and Intelligence Division, , Cancer Council Victoria, ; Melbourne, Australia
                [38 ]ISNI 0000 0001 2188 0957, GRID grid.410445.0, Department of Public Health, John A. Burns School of Medicine, , University of Hawaii at Manoa, ; Manoma, Hawaii United States of America
                [39 ]ISNI 000000041936754X, GRID grid.38142.3c, Department of Epidemiology, Harvard T.H. Chan School of Public Health, , Harvard University, Boston, ; Massachusetts, United States of America
                [40 ]ISNI 000000041936754X, GRID grid.38142.3c, Department of Epidemiology, Nutrition, Harvard T.H. Chan School of Public Health, , Harvard University, Boston, ; Massachusetts, United States of America
                [41 ]ISNI 0000 0001 2163 0069, GRID grid.416738.f, National Institute for Occupational Safety and Health, , Centers for Disease Control and Prevention, Atlanta, ; Georgia, United States of America
                [42 ]ISNI 0000 0001 2163 0069, GRID grid.416738.f, Division of Surveillance, Hazard Evaluations, and Field Studies, , Centers for Disease Control and Prevention, Atlanta, ; Georgia, United States of America
                [43 ]ISNI 0000 0001 1034 3451, GRID grid.12650.30, Department of Public Health and Clinical Medicine, , Faculty of Medicine, Umeå University, ; Umeå, Sweden
                [44 ]ISNI 0000 0004 1936 8753, GRID grid.137628.9, Departments of Population Health and Environmental Medicine, , New York University School of Medicine, New York, ; New York, United States of America
                [45 ]ISNI 0000 0004 0378 8294, GRID grid.62560.37, Department of Medicine, , Brigham and Women’s Hospital, Boston, ; Massachusetts, United States of America
                [46 ]ISNI 0000000122986657, GRID grid.34477.33, Department of Epidemiology, School of Public Health and Community Medicine, , University of Washington, Seattle, ; Washington, United States of America
                Author information
                http://orcid.org/0000-0003-1783-6296
                http://orcid.org/0000-0003-4290-6794
                http://orcid.org/0000-0002-4384-206X
                http://orcid.org/0000-0002-3382-6787
                http://orcid.org/0000-0001-6190-9304
                Article
                24580
                10.1038/s41598-018-24580-z
                5943590
                29743610
                f6071626-3bde-4cbd-bf83-d9a1a1c91b8b
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 2 January 2018
                : 6 April 2018
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