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1. Genetic variants of TSLP and asthma in an admixed urban population.

Author

Mengling Liu, Linda Rogers, Qinyi Cheng, Yongzhao Shao, Maria Elena Fernandez-Beros, Joel N Hirschhorn, Helen N Lyon, Zofia K Z Gajdos, Sailaja Vedantam, Peter Gregersen, Michael F Seldin, Bertram Bleck, Adaikalavan Ramasamy, Anna-Liisa Hartikainen, Marjo-Riitta Jarvelin, Mikko Kuokkanen, Tarja Laitinen, Johan Eriksson, Terho Lehtimäki, Olli T Raitakari, and Joan Reibman

Subjects
Medicine, Science
Abstract

Thymic stromal lymphopoietin (TSLP), an IL7-like cytokine produced by bronchial epithelial cells is upregulated in asthma and induces dendritic cell maturation supporting a Th2 response. Environmental pollutants, including tobacco smoke and diesel exhaust particles upregulate TSLP suggesting that TSLP may be an interface between environmental pollution and immune responses in asthma. Since asthma is prevalent in urban communities, variants in the TSLP gene may be important in asthma susceptibility in these populations.To determine whether genetic variants in TSLP are associated with asthma in an urban admixed population. METHODOLOGY AND MAIN RESULTS: Ten tag-SNPs in the TSLP gene were analyzed for association with asthma using 387 clinically diagnosed asthmatic cases and 212 healthy controls from an urban admixed population. One SNP (rs1898671) showed nominally significant association with asthma (odds ratio (OR) = 1.50; 95% confidence interval (95% CI): 1.09-2.05, p = 0.01) after adjusting for age, BMI, income, education and population stratification. Association results were consistent using two different approaches to adjust for population stratification. When stratified by smoking status, the same SNP showed a significantly increased risk associated with asthma in ex-smokers (OR = 2.00, 95% CI: 1.04-3.83, p = 0.04) but not significant in never-smokers (OR = 1.34; 95% CI: 0.93-1.94, p = 0.11). Haplotype-specific score test indicated that an elevated risk for asthma was associated with a specific haplotype of TSLP involving SNP rs1898671 (OR = 1.58, 95% CI: 1.10-2.27, p = 0.01). Association of this SNP with asthma was confirmed in an independent large population-based cohort consortium study (OR = 1.15, 95% CI: 1.07-1.23, p = 0.0003) and the results stratified by smoking status were also validated (ex-smokers: OR = 1.21, 95% CI: 1.08-1.34, p = 0.003; never-smokers: OR = 1.06, 95% CI: 0.94-1.17, p = 0.33).Genetic variants in TSLP may contribute to asthma susceptibility in admixed urban populations with a gene and environment interaction.

Published
2011
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2. Rapid assessment of genetic ancestry in populations of unknown origin by genome-wide genotyping of pooled samples.

Author

Charleston W K Chiang, Zofia K Z Gajdos, Joshua M Korn, Finny G Kuruvilla, Johannah L Butler, Rachel Hackett, Candace Guiducci, Thutrang T Nguyen, Rainford Wilks, Terrence Forrester, Christopher A Haiman, Katherine D Henderson, Loic Le Marchand, Brian E Henderson, Mark R Palmert, Colin A McKenzie, Helen N Lyon, Richard S Cooper, Xiaofeng Zhu, and Joel N Hirschhorn

Subjects
Genetics, QH426-470
Abstract

As we move forward from the current generation of genome-wide association (GWA) studies, additional cohorts of different ancestries will be studied to increase power, fine map association signals, and generalize association results to additional populations. Knowledge of genetic ancestry as well as population substructure will become increasingly important for GWA studies in populations of unknown ancestry. Here we propose genotyping pooled DNA samples using genome-wide SNP arrays as a viable option to efficiently and inexpensively estimate admixture proportion and identify ancestry informative markers (AIMs) in populations of unknown origin. We constructed DNA pools from African American, Native Hawaiian, Latina, and Jamaican samples and genotyped them using the Affymetrix 6.0 array. Aided by individual genotype data from the African American cohort, we established quality control filters to remove poorly performing SNPs and estimated allele frequencies for the remaining SNPs in each panel. We then applied a regression-based method to estimate the proportion of admixture in each cohort using the allele frequencies estimated from pooling and populations from the International HapMap Consortium as reference panels, and identified AIMs unique to each population. In this study, we demonstrated that genotyping pooled DNA samples yields estimates of admixture proportion that are both consistent with our knowledge of population history and similar to those obtained by genotyping known AIMs. Furthermore, through validation by individual genotyping, we demonstrated that pooling is quite effective for identifying SNPs with large allele frequency differences (i.e., AIMs) and that these AIMs are able to differentiate two closely related populations (HapMap JPT and CHB).

Published
2010
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3. Public Health 101 Nanocourse: A Condensed Educational Tool for Non–Public Health Professionals

Author

Candace C. Nelson, Morteza Asgarzadeh, Myriam C. Afeiche, Usheer Kanjee, Catherine Kreatsoulas, Alberto J. Caban-Martinez, Cherie L. Ramirez, and Zofia K. Z. Gajdos

Subjects
medicine.medical_specialty, Medical education, Schools, Public Health, business.industry, Public health, Public Health, Environmental and Occupational Health, International health, Pilot Projects, Public health informatics, Health policy and management, Health promotion, Massachusetts, Coursework, Commentary, Humans, Medicine, Health education, Curriculum, Public Health, business, Health policy
Abstract

Graduate students and postdoctoral fellows—including those at the Harvard School of Public Health (HSPH)—have somewhat limited opportunities outside of traditional coursework to learn holistically about public health. Because this lack of familiarity could be a barrier to fruitful collaboration across disciplines, HSPH postdocs sought to address this challenge. In response, the Public Health 101 Nanocourse was developed to provide an overview of five core areas of public health (biostatistics, environmental health sciences, epidemiology, health policy and management, and social and behavioral sciences) in a two half-day course format. We present our experiences with developing and launching this novel approach to acquainting wider multidisciplinary audiences with the field of public health.

Published
2015
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4. Genetic determinants of pubertal timing in the general population

Author

Zofia K. Z. Gajdos, Katherine D. Henderson, Joel N. Hirschhorn, and Mark R. Palmert

Subjects
Genetics, education.field_of_study, Developmental stage, Normal puberty, Time Factors, Kallmann syndrome, Puberty, Population, Genetic Diseases, Inborn, Genetic Variation, Biology, medicine.disease, Biochemistry, Article, Genetics, Population, Endocrinology, Hypogonadotropic hypogonadism, Healthy individuals, Genetic variation, medicine, Humans, education, Molecular Biology, Gene
Abstract

Puberty is an important developmental stage during which reproductive capacity is attained. The timing of puberty varies greatly among healthy individuals in the general population and is influenced by both genetic and environmental factors. Although genetic variation is known to influence the normal spectrum of pubertal timing, the specific genes involved remain largely unknown. Genetic analyses have identified a number of genes responsible for rare disorders of pubertal timing such as hypogonadotropic hypogonadism and Kallmann syndrome. Recently, the first loci with common variation reproducibly associated with population variation in the timing of puberty were identified at 6q21 in or near LIN28B and at 9q31.2. However, these two loci explain only a small fraction of the genetic contribution to population variation in pubertal timing, suggesting the need to continue to consider other loci and other types of variants. Here we provide an update of the genes implicated in disorders of puberty, discuss genes and pathways that may be involved in the timing of normal puberty, and suggest additional avenues of investigation to identify genetic regulators of puberty in the general population.

Published
2010
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5. Use of weighted reference panels based on empirical estimates of ancestry for capturing untyped variation

Author

Joel N. Hirschhorn, Sam Tischfield, Laurence N. Kolonel, Christopher A. Haiman, Loic Le Marchand, Brian E. Henderson, Johannah L. Butler, Matthew Egyud, and Zofia K. Z. Gajdos

Subjects
Genetic Markers, Male, Single-nucleotide polymorphism, Genome-wide association study, Ancestry-informative marker, Biology, Polymorphism, Single Nucleotide, Article, Sampling Studies, Cohort Studies, Gene Frequency, Genetic variation, Ethnicity, Genetics, Humans, International HapMap Project, Allele frequency, Alleles, Genetics (clinical), Genetic Variation, Minor allele frequency, Evolutionary biology, Female, Databases, Nucleic Acid, Imputation (genetics), Genome-Wide Association Study
Abstract

Many association methods use a subset of genotyped single nucleotide polymorphisms (SNPs) to capture or infer genotypes at other untyped SNPs. We and others previously showed that tag SNPs selected to capture common variation using data from The International HapMap Consortium (Nature 437:1299-1320, 2005), The International HapMap Consortium (Nature 449:851-861, 2007) could also capture variation in populations of similar ancestry to HapMap reference populations (de Bakker et al. in Nat Genet 38:1298-1303, 2006; González-Neira et al. in Genome Res 16:323-330, 2006; Montpetit et al. in PLoS Genet 2:282-290, 2006; Mueller et al. in Am J Hum Genet 76:387-398, 2005). To capture variation in admixed populations or populations less similar to HapMap panels, a "cosmopolitan approach," in which all samples from HapMap are used as a single reference panel, was proposed. Here we refine this suggestion and show that use of a "weighted reference panel," constructed based on empirical estimates of ancestry in the target population (relative to available reference panels), is more efficient than the cosmopolitan approach. Weighted reference panels capture, on average, only slightly fewer common variants (minor allele frequency5%) than the cosmopolitan approach (mean r (2) = 0.977 vs. 0.989, 94.5% variation captured vs. 96.8% at r (2)0.8), across the five populations of the Multiethnic Cohort, but entail approximately 25% fewer tag SNPs per panel (average 538 vs. 718). These results extend a recent study in two Indian populations (Pemberton et al. in Ann Hum Genet 72:535-546, 2008). Weighted reference panels are potentially useful for both the selection of tag SNPs in diverse populations and perhaps in the design of reference panels for imputation of untyped genotypes in genome-wide association studies in admixed populations.

Published
2009
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6. Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks

Author

Joachim Heinrich, Arthur W. Musk, Dan L. Nicolae, Magnus Wickman, Anita L. Kozyrskyj, George T. O'Connor, Sven Michel, John Beilby, Nicole Probst-Hensch, André G. Uitterlinden, Ulrike Gehring, Eugene R. Bleecker, Markku Heliövaara, Christer Janson, Janine Altmüller, Tatsuhiko Tsunoda, Kathleen C. Barnes, Johan G. Eriksson, Alexey Polonikov, Penelope E. Graves, Andrea von Berg, Philip J. Thompson, Sina A. Gharib, Johan C. de Jongste, Miriam F. Moffatt, Adaikalavan Ramasamy, Kristin M. Burkart, Thomas J. Hudson, Marjo-Riitta Järvelin, Rasika A. Mathias, Kathleen M. Donohue, Gonneke Willemsen, Yuliya Fedorova, Michael Kabesch, Jing Hua Zhao, Ashok Kumar, Kenji Matsumoto, Vivi Schlünssen, Dara G. Torgerson, Terri H. Beaty, Florence Demenais, Julie E. Park, Tari Haahtela, Aarno Palotie, Elisabeth Widen, Hamida Mohamdi, Vladimir P. Ivanov, Tarja Laitinen, Emiko Noguchi, Lewis J. Smith, Valérie Siroux, Christopher E. Brightling, P. A. Selivanova, Frank D. Gilliland, Johannes Waage, Deborah A. Meyers, Unnur Thorsteinsdottir, Melanie C. Matheson, Hiroshi Hirose, Sébastien Letort, Andrew Bush, Alan James, Kari Stefansson, Robert A. Scott, Isabelle Romieu, Mads Melbye, Albert M. Levin, Laura R. Loehr, Guo Li, Veikko Salomaa, Celeste Eng, Esteban G. Burchard, Ralf J. P. van der Valk, Bjarke Feenstra, Daan W. Loth, Atsushi Takahashi, Lies Lahousse, Denise Daley, Stephen S. Rich, Carla M. T. Tiesler, Liming Liang, L. Keoki Williams, Susanne Lau, Nicholas J. Wareham, Erik Melén, Cameron D. Palmer, Medea Imboden, Patricia Margaritte-Jeannin, Unnur S. Bjornsdottir, Ludmila M. Ogorodova, Erika von Mutius, Gerard H. Koppelman, Susan R. Heckbert, Rachel A. Myers, Martin Farrall, Moira Chan-Yeung, Jim Gauderman, Frank Geller, Sailaja Vedantam, Rajesh Kumar, Kian Fan Chung, Jon Genuneit, John Henderson, David B. Kantor, Carole Ober, Alexessander Couto Alves, Craig E. Pennell, Inge M. Wouters, Catherine Laprise, Terho Lehtimäki, Colin F. Robertson, Emmanuelle Bouzigon, Maxim B. Freidin, William O.C.M. Cookson, Bruno H. Stricker, John A. Curtin, Albert Hofman, Muhammad T. Salam, Blanca E. Del-Rio-Navarro, Young-Ae Lee, Liesbeth Duijts, Klaus Bønnelykke, Vincent W. V. Jaddoe, Göran Pershagen, Dirkje S. Postma, Pekka Jousilahti, Hans Bisgaard, Dorret I. Boomsma, Amaury Vaysse, Deborah Jarvis, Maria Solodilova, Gudmar Thorleifsson, James J. Yang, V. P. Puzyrev, Manuel A. R. Ferreira, Maartje A.E. Nieuwenhuis, Jouke J. Hottenga, Ingileif Jonsdottir, Graham Jones, Myriam Brossard, Jennie Hui, Judith M. Vonk, Allan B. Becker, Elza Khusnutdinova, Wendy L. McArdle, Benjamin A. Raby, Olli T. Raitakari, Wendy B. White, Mark Lathrop, Adnan Custovic, Ingo Marenholz, Joel N. Hirschhorn, Fernando J. Martinez, Mikko Kuokkanen, Michiaki Kubo, Patrick G. Holt, Torben Sigsgaard, Eskil Kreiner, Stephanie J. London, Daniel F. Gudbjartsson, Mika Kähönen, Guy Brusselle, Blanca E. Himes, R. Graham Barr, Scott T. Weiss, David P. Strachan, Hamdi Mbarek, Wei Ang, A. S. Karunas, Marie Standl, Angela Simpson, Dick Heederik, Zofia K. Z. Gajdos, Raquel Granell, Ani Manichaikul, Fondation Jean-Dausset-CEPH, INSERM U946, Institut National de la Santé et de la Recherche Médicale (INSERM), Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Medicine [Aurora, CO, USA], University of Colorado [Denver], National Heart and Lung Institute (NHLI), Imperial College London, Cologne Center for Genomics (CCG), Cologne Center for Genomics-University of Cologne, Johns Hopkins University (JHU), Pediatrics and Child Health, University of Manitoba [Winnipeg], University of Arizona, King‘s College London, Méthodologie statistique et épidémiologie génétique de maladies multifactorielles, Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Respiratory Medicine and Thoracic Surgery, University of Leicester-Institute for Lung Health, Ghent University Hospital, Department of Paediatric Respiratory Medicine, Imperial College London-Royal Brompton Hospital-National Heart and Lung Institute [UK], Airway Disease Section, National Heart and Lung Institute, The Generation R Study group, Erasmus University Medical Centre, Medstar Research Institute, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Université Paris-Sorbonne - Paris 4 - École supérieure du professorat et de l'éducation - Académie de Paris (ESPE Paris), Université Paris-Sorbonne (UP4), Population Genetics Laboratory [Tomsk, Russia], Research Institute for Medical Genetics [Tomsk, Russia], University of Southern California (USC), Utrecht University [Utrecht], Institute of Epidemiology, Universität Ulm - Ulm University [Ulm, Allemagne], MRC Integrative Epidemiology Unit [Bristol, Royaume-Uni] (MRC IEU), University of Bristol [Bristol], Arizona Respiratory Center, Helsinki University Hospital, Division of Occupational and Environmental Health, Institute for Risk Assessment (IRAS), Ludwig Maximilian University [Munich] (LMU), National Institute of Health and Welfare, MRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Department of Mathematics, University of Warwick, Warwick Mathematics Institute (WMI), University of Warwick [Coventry]-University of Warwick [Coventry], Sir Charles Gairdner Hospital, Swiss Tropical and Public Health Institute [Basel], The Generation R Study, Pediatrics, Epidemiology, Uppsala University, Institute of Health Sciences and Biocenter Oulu, University of Oulu, Tampere University Hospital, Institute of Biochemistry and Genetics of Ufa Scientific Centre, Russian Academy of Sciences [Moscow] (RAS), Pediatric Pulmonology, Allergology & Epidemiology, University of Groningen [Groningen]-University Medical Center Groningen [Groningen] (UMCG)-Beatrix Children's Hospital-Groningen Research Institute for Asthma and COPD, National Center for Atmospheric Research [Boulder] (NCAR), Epidemiology & Public Health, Swiss Tropical and Public Health Institute [Basel]-Medical School University of Basel, Department of Respiratory Medicine, Departments of Pulmonary Medicine and Medical Genetics, Université du Québec à Chicoutimi (UQAC), McGill University and Genome Quebec Innovation Centre, Department of Pediatric Pneumology and Immunology, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Faculty of Medicine and Life Sciences [Tampere], University of Tampere [Finland], Laboratoire des interactions plantes micro-organismes (LIPM), Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), China Agricultural University (CAU), Harvard School of Public Health, Department of Epidemiology, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC)-UNC Gillings School of Global Public Health-Carolina Center for Genome Sciences, National Institute for Environmental Health Sciences Research Triangle Park, National Institute for Materials Science (NIMS), Dept. of Epidemiology Research, Statens Serum Institut [Copenhagen], Institute of Environmental Medicine [Stockholm, Sweden], Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm]-Astrid Lindgren Children's Hospital, Center for Human Genomics, Wake Forest University, Université de Tsukuba = University of Tsukuba, Head of Medical Sequencing, Institute of environmental medicine, Karolinska Institute, Respiratory Epidemiology and Public Health, Imperial College London-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU)-MRC-HPA Centre for Environment and Health, Centre International de Recherche contre le Cancer (CIRC), Department of Chronic Disease Prevention, National Institute for Health and Welfare [Helsinki], Aarhus University [Aarhus], Institute of Metabolic Science, MRC, Section of Environment Occupation & Health, University of Manchester [Manchester], Epidémiologie et Biostatistique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), deCODE Genetics, deCODE genetics [Reykjavik], Population Health Sciences and Education, St George's University of London, Drug Safety Unit, Inspectorate for Health Care, Tohoku University [Sendai], Department of Oceanography, University of Hawai‘i [Mānoa] (UHM), University of California [San Francisco] (UCSF), University of California, Asthma and Allergy Department, University Children's Hospital-Ludwig Maximilians University, IT University of Copenhagen, MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge [UK] (CAM), Sachs’ Children and Youth Hospital [Stockholm, Sweden], Genetic Epidemiology Unit, Addenbrooke's Hospital, University of Illinois [Chicago] (UIC), University of Illinois System, Titu Maiorescu University Bucharest, Titu Maiorescu University = Universitatea Titu Maiorescu [Buchares] (UTM), Pulmonary Medicine, Erasmus MC other, Internal Medicine, Biological Psychology, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Vaysse, Amaury, University of Oxford, University of California [San Francisco] (UC San Francisco), University of California (UC), University Children's Hospital-Ludwig-Maximilians University [Munich] (LMU), IT University of Copenhagen (ITU), Groningen Research Institute for Asthma and COPD (GRIAC), Medical Research Council (MRC), National Institute for Health Research, Wellcome Trust, Wareham, Nicholas [0000-0003-1422-2993], Zhao, Jing Hua [0000-0003-4930-3582], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, HAY-FEVER, Netherlands Twin Register (NTR), [SDV]Life Sciences [q-bio], Genome-wide association study, [SDV.GEN] Life Sciences [q-bio]/Genetics, VARIANTS, Australian Asthma Genetics Consortium (AAGC) collaborators, Epigenesis, Genetic, 0302 clinical medicine, Pleiotropy, immune system diseases, Leukocytes, Promoter Regions, Genetic, AUTOIMMUNE-DISEASE, 11 Medical and Health Sciences, ComputingMilieux_MISCELLANEOUS, Genetics & Heredity, 3. Good health, Histone Code, [SDV] Life Sciences [q-bio], Enhancer Elements, Genetic, Phenotype, TWINS, Hay fever, POPULATIONS, Life Sciences & Biomedicine, Risk, EXPRESSION, Coronacrisis-Taverne, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, 03 medical and health sciences, Immune system, SDG 3 - Good Health and Well-being, medicine, Genetics, Journal Article, Humans, Genetic Predisposition to Disease, Allele, GENOME-WIDE ASSOCIATION, Alleles, METAANALYSIS, Genetic association, Asthma, Autoimmune disease, [SDV.GEN]Life Sciences [q-bio]/Genetics, Science & Technology, Rhinitis, Allergic, Seasonal, 06 Biological Sciences, medicine.disease, GENE, respiratory tract diseases, 030104 developmental biology, 030228 respiratory system, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Genetic Loci, Immunology, Developmental Biology, Genome-Wide Association Study
Abstract

We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.

Published
2018
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7. Genome-wide association study of age at menarche in African-American women

Author

Charles Kooperberg, Nancy Fugate Woods, Sandra L. Deming, Joel N. Hirschhorn, Kari E. North, Elisa V. Bandera, Erin N. Smith, Christopher A. Haiman, Zhao Chen, Michael F. Press, Leslie Bernstein, Sarah S. Murray, Loic Le Marchand, Alice M. Arnold, Robert C. Millikan, Sathanur R. Srinivasan, Laurence N. Kolonel, Esther M. John, Julie R. Palmer, Nora Franceschini, Gary Chen, Christine B. Ambrosone, Gerald S. Berenson, Regina G. Ziegler, Ellen W. Demerath, Zofia K. Z. Gajdos, Gerardo Heiss, Joanne M. Murabito, Jorge L. Rodriquez-Gil, Anne R. Cappola, Stephen J. Chanock, Michelle K. Evans, Cathy E. Elks, Christina T. L. Chen, Sarah J. Nyante, L. Adrienne Cupples, Tomi Pastinen, Edward A. Ruiz-Narváez, B. Gwen Windham, Xiaoning Lu, Christopher S. Carlson, Ching-Ti Liu, Melissa Wellons, Jennifer J. Hu, Nicholas J. Schork, Angela Britton, Mike A. Nalls, Alan B. Zonderman, Wei Chen, Aleksandar Rajkovic, Sue A. Ingles, Nora L. Nock, Wei Zheng, Kathleen F. Kerr, Brian E. Henderson, and Solomon K. Musani

Subjects
Aging, Genome-wide association study, Type 2 diabetes, Medical and Health Sciences, Risk Factors, Group F, 2.1 Biological and endogenous factors, Aetiology, Child, Genetics (clinical), Genetics, African Americans, Genetics & Heredity, Membrane Glycoproteins, Association Studies Articles, Nuclear Receptor Subfamily 1, Group F, Member 1, General Medicine, Single Nucleotide, Biological Sciences, Menarche, Female, Type 2, Member 1, Adolescent, Nuclear Receptor Subfamily 1, Single-nucleotide polymorphism, Locus (genetics), Biology, Population stratification, Polymorphism, Single Nucleotide, White People, Young Adult, medicine, Diabetes Mellitus, SNP, Humans, Obesity, Polymorphism, Molecular Biology, Whites, Prevention, Contraception/Reproduction, Human Genome, Membrane Proteins, Genetic Variation, medicine.disease, Black or African American, Diabetes Mellitus, Type 2, Genetic Loci, Case-Control Studies, Linear Models, Demography, Genome-Wide Association Study
Abstract

African-American (AA) women have earlier menarche on average than women of European ancestry (EA), and earlier menarche is a risk factor for obesity and type 2 diabetes among other chronic diseases. Identification of common genetic variants associated with age at menarche has a potential value in pointing to the genetic pathways underlying chronic disease risk, yet comprehensive genome-wide studies of age at menarche are lacking for AA women. In this study, we tested the genome-wide association of self-reported age at menarche with common single-nucleotide polymorphisms (SNPs) in a total of 18 089 AA women in 15 studies using an additive genetic linear regression model, adjusting for year of birth and population stratification, followed by inverse-variance weighted meta-analysis (Stage 1). Top meta-analysis results were then tested in an independent sample of 2850 women (Stage 2). First, while no SNP passed the pre-specified P < 5 × 10(-8) threshold for significance in Stage 1, suggestive associations were found for variants near FLRT2 and PIK3R1, and conditional analysis identified two independent SNPs (rs339978 and rs980000) in or near RORA, strengthening the support for this suggestive locus identified in EA women. Secondly, an investigation of SNPs in 42 previously identified menarche loci in EA women demonstrated that 25 (60%) of them contained variants significantly associated with menarche in AA women. The findings provide the first evidence of cross-ethnic generalization of menarche loci identified to date, and suggest a number of novel biological links to menarche timing in AA women.

Published
2013

8. Replication and fine mapping of asthma-associated loci in individuals of African ancestry

Author

David B. Kantor, Yan Meng, Taylor Young, Laura R. Loehr, Alkes L. Price, Kristin M. Burkart, George J. Papanicolaou, Susan R. Heckbert, Lewis J. Smith, Marcy F. Petrini, Helen N. Lyon, George T. O'Connor, Rajesh Kumar, Cameron D. Palmer, Stephanie J. London, Zofia K. Z. Gajdos, Joel N. Hirschhorn, David R. Jacobs, Wendy B. White, Samuela Pollack, and R. Graham Barr

Subjects
Male, Linkage disequilibrium, Candidate gene, Genotype, Black People, Single-nucleotide polymorphism, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Article, Genetic variation, Genetics, Humans, Genetic Predisposition to Disease, Genetics (clinical), Genetic Association Studies, Genetic association, Receptors, Interleukin-18, Interleukin-13, Chromosomes, Human, Pair 10, Genetic Variation, Membrane Proteins, Receptors, Interleukin-1, Human genetics, Asthma, Acid Anhydride Hydrolases, Neoplasm Proteins, DNA-Binding Proteins, DNA Repair Enzymes, Genetic Loci, Female
Abstract

Asthma originates from genetic and environmental factors with about half the risk of disease attributable to heritable causes. Genome-wide association studies, mostly in populations of European ancestry, have identified numerous asthma-associated single nucleotide polymorphisms (SNPs). Studies in populations with diverse ancestries allow both for identification of robust associations that replicate across ethnic groups and for improved resolution of associated loci due to different patterns of linkage disequilibrium between ethnic groups. Here we report on an analysis of 745 African-American subjects with asthma and 3,238 African-American control subjects from the Candidate Gene Association Resource (CARe) Consortium, including analysis of SNPs imputed using 1,000 Genomes reference panels and adjustment for local ancestry. We show strong evidence that variation near RAD50/IL13, implicated in studies of European ancestry individuals, replicates in individuals largely of African ancestry. Fine mapping in African ancestry populations also refined the variants of interest for this association. We also provide strong or nominal evidence of replication at loci near ORMDL3/GSDMB, IL1RL1/IL18R1, and 10p14, all previously associated with asthma in European or Japanese populations, but not at the PYHIN1 locus previously reported in studies of African-American samples. These results improve the understanding of asthma genetics and further demonstrate the utility of genetic studies in populations other than those of largely European ancestry.

Published
2013

9. Correction: Genome-Wide Association Studies of Asthma in Population-Based Cohorts Confirm Known and Suggested Loci and Identify an Additional Association near HLA

Author

Marjo-Riitta Järvelin, Kay-Tee Khaw, Veikko Salomaa, Colin F. Robertson, Jing Hua Zhao, Guy B. Marks, Adaikalavan Ramasamy, Christer Janson, Tarja Laitinen, Cameron D. Palmer, Grant W. Montgomery, Jaana Laitinen, Melanie C. Matheson, Tari Haahtela, Terho Lehtimäki, Mika Kähönen, Michael J. Abramson, Johan G. Eriksson, George T. O'Connor, Andrew C. Heath, Jorma S. A. Viikari, Manuel A. R. Ferreira, Helen N. Lyon, Philip J. Thompson, Nicholas G. Martin, Lachlan J. M. Coin, Aarno Palotie, Shyamali C. Dharmage, Elisabeth Widen, Juha Pekkanen, Olli T. Raitakari, Nicholas J. Wareham, Joel N. Hirschhorn, Peter N. Le Souëf, Alexessander Couto Alves, Matthew A. Brown, David L. Duffy, Mikko Kuokkanen, Pamela A. F. Madden, David P. Strachan, Zofia K. Z. Gajdos, Matthias Wjst, Sailaja Vedantam, Anneli Pouta, Pekka Jousilahti, Deborah Jarvis, Department of Dermatology, Allergology and Venereology, Clinicum, Institute for Molecular Medicine Finland, Haartman Institute (-2014), Department of Medical and Clinical Genetics, Department of General Practice and Primary Health Care, Genomics of Neurological and Neuropsychiatric Disorders, Genomic Discoveries and Clinical Translation, and Medical Research Council (MRC)

Subjects
Medicin och hälsovetenskap, Pulmonology, Population genetics, lcsh:Medicine, Genome-wide association study, VARIANTS, SUSCEPTIBILITY, Medical and Health Sciences, Cohort Studies, 0302 clinical medicine, HLA Antigens, Risk Factors, Genetics of the Immune System, lcsh:Science, Genetics, ROR-ALPHA, 0303 health sciences, Multidisciplinary, Allergy and Hypersensitivity, CARDIOVASCULAR RISK, Middle Aged, 3. Good health, Multidisciplinary Sciences, ALLERGY, DISEASES, Science & Technology - Other Topics, HEART, Medicine, HEALTH, Occupational asthma, Research Article, Adult, GENES, General Science & Technology, Quantitative Trait Loci, Immunology, Australian Asthma Genetics Consortium collaborators, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Molecular Genetics, 03 medical and health sciences, Gene interaction, MD Multidisciplinary, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, METAANALYSIS, 030304 developmental biology, Genetic association, Science & Technology, lcsh:R, Correction, Computational Biology, Human Genetics, ta3121, medicine.disease, Human genetics, Asthma, 030228 respiratory system, Genetics of Disease, Clinical Immunology, lcsh:Q, 3111 Biomedicine, LUNG, Population Genetics, Genome-Wide Association Study
Abstract

RATIONALE: Asthma has substantial morbidity and mortality and a strong genetic component, but identification of genetic risk factors is limited by availability of suitable studies. \ud \ud OBJECTIVES: To test if population-based cohorts with self-reported physician-diagnosed asthma and genome-wide association (GWA) data could be used to validate known associations with asthma and identify novel associations.\ud \ud METHODS: The APCAT (Analysis in Population-based Cohorts of Asthma Traits) consortium consists of 1,716 individuals with asthma and 16,888 healthy controls from six European-descent population-based cohorts. We examined associations in APCAT of thirteen variants previously reported as genome-wide significant (P

Published
2012

10. The efficacy of detecting variants with small effects on the Affymetrix 6.0 platform using pooled DNA

Author

Zofia K. Z. Gajdos, Xiaofeng Zhu, Joel N. Hirschhorn, Thutrang T. Nguyen, Joshua M. Korn, Brian E. Henderson, Christopher A. Haiman, Terrence Forrester, Katherine D. Henderson, Rachel Hackett, Richard S. Cooper, Candace Guiducci, Loic Le Marchand, Johannah L. Butler, Rainford J. Wilks, Mark R. Palmert, Helen N. Lyon, Charleston W. K. Chiang, and Colin A. McKenzie

Subjects
Male, Adolescent, Pooling, Single-nucleotide polymorphism, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Article, Cohort Studies, Genotype, Genetics, Humans, Computer Simulation, Obesity, Child, Genotyping, Genetics (clinical), Oligonucleotide Array Sequence Analysis, Menarche, Genetic Variation, Sequence Analysis, DNA, Human genetics, SNP genotyping, Female, SNP array, Genome-Wide Association Study
Abstract

Genome-wide genotyping of a cohort using pools rather than individual samples has long been proposed as a cost-saving alternative for performing genome-wide association (GWA) studies. However, successful disease gene mapping using pooled genotyping has thus far been limited to detecting common variants with large effect sizes, which tend not to exist for many complex common diseases or traits. Therefore, for DNA pooling to be a viable strategy for conducting GWA studies, it is important to determine whether commonly used genome-wide SNP array platforms such as the Affymetrix 6.0 array can reliably detect common variants of small effect sizes using pooled DNA. Taking obesity and age at menarche as examples of human complex traits, we assessed the feasibility of genome-wide genotyping of pooled DNA as a single-stage design for phenotype association. By individually genotyping the top associations identified by pooling, we obtained a 14- to 16-fold enrichment of SNPs nominally associated with the phenotype, but we likely missed the top true associations. In addition, we assessed whether genotyping pooled DNA can serve as an inexpensive screen as the second stage of a multi-stage design with a large number of samples by comparing the most cost-effective 3-stage designs with 80% power to detect common variants with genotypic relative risk of 1.1, with and without pooling. Given the current state of the specific technology we employed and the associated genotyping costs, we showed through simulation that a design involving pooling would be 1.07 times more expensive than a design without pooling. Thus, while a significant amount of information exists within the data from pooled DNA, our analysis does not support genotyping pooled DNA as a means to efficiently identify common variants contributing small effects to phenotypes of interest. While our conclusions were based on the specific technology and study design we employed, the approach presented here will be useful for evaluating the utility of other or future genome-wide genotyping platforms in pooled DNA studies.

Published
2011

11. Genome-wide association studies: results from the first few years and potential implications for clinical medicine

Author

Joel N. Hirschhorn and Zofia K. Z. Gajdos

Subjects
Multifactorial Inheritance, Genetic Linkage, Population, Genome-wide association study, Hyperlipidemias, Biology, Quantitative trait locus, General Biochemistry, Genetics and Molecular Biology, Predictive medicine, Genetic variation, Humans, Genetic Predisposition to Disease, Autistic Disorder, Precision Medicine, education, Fetal Hemoglobin, Genetics, education.field_of_study, Genetic Variation, General Medicine, Inflammatory Bowel Diseases, Human genetics, Body Height, Diabetes Mellitus, Type 2, Polygene, Clinical Medicine, Genome-Wide Association Study
Abstract

Most common diseases and quantitative traits are heritable: determined in part by genetic variation within the population. The inheritance is typically polygenic in that combined effects of variants in numerous genes, plus nongenetic factors, determine outcome. The genes influencing common disease and quantitative traits remained largely unknown until the implementation in 2006 of genome-wide association (GWA) studies that comprehensively surveyed common genetic variation (frequency >5%). By 2010, GWA studies identified >1,000 genetic variants for polygenic traits. Typically, these variants together account for a modest fraction (10%–30%) of heritability, but they have highlighted genes in both known and new biological pathways and genes of unknown function. This initial effort prefigures new studies aimed at rarer variation and decades of functional work to decipher newly glimpsed biology. The greatest impact of GWA studies may not be in predictive medicine but rather in the development over the next decades of therapies based on novel biological insights.

Published
2011

12. Association Studies of Common Variants in 10 Hypogonadotropic Hypogonadism Genes with Age at Menarche

Author

David Reich, Peter E. Clayton, Katherine D. Henderson, Alkes L. Price, Johannah L. Butler, Brian E. Henderson, Loic Le Marchand, Zofia K. Z. Gajdos, Joel N. Hirschhorn, Matthew Egyud, Chunyan He, Mark R. Palmert, David J. Hunter, and Pamela J. Supelak

Subjects
medicine.medical_specialty, Adolescent, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Population, Context (language use), Biology, Biochemistry, Hawaii, Body Mass Index, Endocrinology, Hypogonadotropic hypogonadism, Internal medicine, Surveys and Questionnaires, Genotype, Genetic variation, medicine, Humans, Genetic variability, Receptor, Fibroblast Growth Factor, Type 1, education, Child, Genetic association, Menarche, Puberty, Delayed, education.field_of_study, Hypogonadism, Biochemistry (medical), Puberty, Racial Groups, Age Factors, Genetic Variation, medicine.disease, Los Angeles, Female, Original Article, Receptors, LHRH
Abstract

Context: Although the timing of puberty is a highly heritable trait, little is known about the genes that regulate pubertal timing in the general population. Several genes have been identified that, when mutated, cause disorders of delayed or absent puberty such as hypogonadotropic hypogonadism (HH).Objective: Because severe variants in HH-related genes cause a severe puberty phenotype, we hypothesized that common subtle variation in these genes could contribute to the population variation in pubertal timing.Design: We assessed common genetic variation in 10 HH-related genes in 1801 women from the Hawaii and Los Angeles Multiethnic Cohort with either early (age < 11 yr) or late (age > 14 yr) menarche and in other replication samples. In addition to these common variants, we also studied the most frequently reported HH mutations to assess their role in the population variation in pubertal timing.Setting and Patients/Other Participants: Within the general community, 1801 women from the Hawaii and Los Angeles Multiethnic Cohort participated.Main Outcome Measures: We assessed the association of genetic variation with age at menarche.Results: We found no significant association between any of the variants tested and age at menarche, although we cannot rule out modest effects of these variants or of other variants at long distances from the coding region. In several self-reported racial/ethnic groups represented in our study, we observed an association between estimated genetic ancestry and age at menarche.Conclusions: Our results suggest that common variants near 10 HH-related loci do not play a substantial role in the regulation of age at menarche in the general population.

Published
2008

13. Public health 101 nanocourse: a condensed educational tool for non-public health professionals.

Author

Ramirez CL, Gajdos ZK, Kreatsoulas C, Afeiche MC, Asgarzadeh M, Nelson CC, Kanjee U, and Caban-Martinez AJ

Subjects
Humans, Massachusetts, Pilot Projects, Schools, Public Health organization & administration, Curriculum, Public Health education
Abstract

Graduate students and postdoctoral fellows-including those at the Harvard School of Public Health (HSPH)-have somewhat limited opportunities outside of traditional coursework to learn holistically about public health. Because this lack of familiarity could be a barrier to fruitful collaboration across disciplines, HSPH postdocs sought to address this challenge. In response, the Public Health 101 Nanocourse was developed to provide an overview of five core areas of public health (biostatistics, environmental health sciences, epidemiology, health policy and management, and social and behavioral sciences) in a two half-day course format. We present our experiences with developing and launching this novel approach to acquainting wider multidisciplinary audiences with the field of public health.

Published
2015
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