A Sex-Stratified Genome-Wide Association Study of Tuberculosis Using a Multi-Ethnic Genotyping Array

Tuberculosis (TB), caused by Mycobacterium tuberculosis, is a complex disease with a known human genetic component. Males seem to be more affected than females and in most countries the TB notification rate is twice as high in males as in females. While socio-economic status, behaviour and sex hormones influence the male bias they do not fully account for it. Males have only one copy of the X chromosome, while diploid females are subject to X chromosome inactivation. In addition, the X chromosome codes for many immune-related genes, supporting the hypothesis that X-linked genes could contribute to TB susceptibility in a sex-biased manner. We report the first TB susceptibility genome-wide association study (GWAS) with a specific focus on sex-stratified autosomal analysis and the X chromosome. Individuals from an admixed South African population were genotyped using the Illumina Multi Ethnic Genotyping Array, specifically designed as a suitable platform for diverse and admixed populations. Association testing was done on the autosome and X chromosome in a sex stratified and combined manner. SNP association testing was not statistically significant using a stringent cut-off for significance but revealed likely candidate genes that warrant further investigation. A genome wide interaction analysis detected 16 significant interactions. Finally, the results highlight the importance of sex-stratified analysis as strong sex-specific effects were identified on both the autosome and X chromosome.

[1]  A. Morris,et al.  Genome-wide association analyses identifies a susceptibility locus for tuberculosis on chromosome 18 q 11 . 2 , 2019 .

[2]  C. Garlanda,et al.  Sexual Dimorphism in Innate Immunity , 2019, Clinical Reviews in Allergy & Immunology.

[3]  Biao Xu,et al.  Discovery of susceptibility loci associated with tuberculosis in Han Chinese , 2017, Human molecular genetics.

[4]  Elizabeth G. Atkinson,et al.  An Unexpectedly Complex Architecture for Skin Pigmentation in Africans , 2017, Cell.

[5]  T. Mushiroda,et al.  Pathogen lineage-based genome-wide association study identified CD53 as susceptible locus in tuberculosis , 2017, Journal of Human Genetics.

[6]  Heng Xiao,et al.  The role of the ATP2C1 gene in Hailey–Hailey disease , 2017, Cellular and Molecular Life Sciences.

[7]  Wei Zhou,et al.  RMP promotes epithelial-mesenchymal transition through NF-κB/CSN2/Snail pathway in hepatocellular carcinoma , 2017, Oncotarget.

[8]  R. Xavier,et al.  The ubiquitin-ligase Smurf1 functions in selective autophagy of M. tuberculosis and anti-tuberculous host defense , 2017 .

[9]  R. Xavier,et al.  The Ubiquitin Ligase Smurf1 Functions in Selective Autophagy of Mycobacterium tuberculosis and Anti-tuberculous Host Defense. , 2017, Cell host & microbe.

[10]  Wei Niu,et al.  Long Non-Coding RNA: Potential Diagnostic and Therapeutic Biomarker for Major Depressive Disorder , 2016, Medical science monitor : international medical journal of experimental and clinical research.

[11]  W. Dreschler,et al.  Mutations in TBL1X Are Associated With Central Hypothyroidism , 2016, The Journal of clinical endocrinology and metabolism.

[12]  Christopher R. Gignoux,et al.  Fine-Scale Human Population Structure in Southern Africa Reflects Ecogeographic Boundaries , 2016, Genetics.

[13]  Kyung-Chul Choi,et al.  SUMOylation of TBL1 and TBLR1 promotes androgen-independent prostate cancer cell growth , 2016, Oncotarget.

[14]  R. Wolff,et al.  Impact of polymorphisms in microRNA biogenesis genes on colon cancer risk and microRNA expression levels: a population-based, case-control study , 2016, BMC Medical Genomics.

[15]  Rafal S. Sobota,et al.  A Locus at 5q33.3 Confers Resistance to Tuberculosis in Highly Susceptible Individuals. , 2016, American journal of human genetics.

[16]  Kenneth Lange,et al.  Efficient analysis of large datasets and sex bias with ADMIXTURE , 2016, BMC Bioinformatics.

[17]  Christopher R. Gignoux,et al.  Fine-scale human population structure in southern Africa reflects ecological boundaries , 2016, bioRxiv.

[18]  C. Deswarte,et al.  A genome-wide association study of pulmonary tuberculosis in Morocco , 2016, Human Genetics.

[19]  T. Zhao,et al.  Duplication of 10q22.3–q23.3 encompassing BMPR1A and NGR3 associated with congenital heart disease, microcephaly, and mild intellectual disability , 2015, American journal of medical genetics. Part A.

[20]  T. Bourgeron,et al.  11q24.2‐25 micro‐rearrangements in autism spectrum disorders: Relation to brain structures , 2015, American journal of medical genetics. Part A.

[21]  Lauren C. Chong,et al.  Genomic Alterations in CIITA Are Frequent in Primary Mediastinal Large B Cell Lymphoma and Are Associated with Diminished MHC Class II Expression. , 2015, Cell reports.

[22]  M. Daya,et al.  TLR1, 2, 4, 6 and 9 Variants Associated with Tuberculosis Susceptibility: A Systematic Review and Meta-Analysis , 2015, PloS one.

[23]  Gabor T. Marth,et al.  An integrated map of structural variation in 2,504 human genomes , 2015, Nature.

[24]  Le A. Trinh,et al.  Nanobody-targeted E3-ubiquitin ligase complex degrades nuclear proteins , 2015, Scientific Reports.

[25]  P. V. van Helden,et al.  Association of toll-like receptors with susceptibility to tuberculosis suggests sex-specific effects of TLR8 polymorphisms. , 2015, Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases.

[26]  Lisa J. Martin,et al.  Genomic architecture of asthma differs by sex. , 2015, Genomics.

[27]  J. Barrett,et al.  Susceptibility to tuberculosis is associated with variants in the ASAP1 gene encoding a regulator of dendritic cell migration , 2015, Nature Genetics.

[28]  N. Rosenberg,et al.  Beyond 2/3 and 1/3: The Complex Signatures of Sex-Biased Admixture on the X Chromosome , 2015, Genetics.

[29]  S. Ahmad,et al.  TLR8 gene polymorphism and association in bacterial load in southern Punjab of Pakistan: an association study with pulmonary tuberculosis , 2015, International journal of immunogenetics.

[30]  A. Keinan,et al.  XWAS: A Software Toolset for Genetic Data Analysis and Association Studies of the X Chromosome , 2014, bioRxiv.

[31]  M. Daya,et al.  TLR 1 , 2 , 4 , 6 and 9 Variants Associated with Tuberculosis Susceptibility : A Systematic Review and Meta-Analysis , 2015 .

[32]  S. Klein,et al.  Sex-based differences in immune function and responses to vaccination. , 2015, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[33]  P. V. van Helden,et al.  Investigating the Role of Gene-Gene Interactions in TB Susceptibility , 2015, PloS one.

[34]  Christopher R. Gignoux,et al.  Using multi-way admixture mapping to elucidate TB susceptibility in the South African Coloured population , 2014, BMC Genomics.

[35]  Aaron J. Sams,et al.  Accounting for eXentricities: Analysis of the X Chromosome in GWAS Reveals X-Linked Genes Implicated in Autoimmune Diseases , 2014, bioRxiv.

[36]  Jian Wang,et al.  X‐Chromosome Genetic Association Test Accounting for X‐Inactivation, Skewed X‐Inactivation, and Escape from X‐Inactivation , 2014, Genetic epidemiology.

[37]  S. M. Hashemi-Shahri,et al.  Association Between TLR8 and TLR9 Gene Polymorphisms and Pulmonary Tuberculosis , 2014 .

[38]  J. Hanover,et al.  Chromosome Imbalance as a Driver of Sex Disparity in Disease , 2014, Journal of genomics.

[39]  S. Narayanan,et al.  Cell death paradigms in the pathogenesis of Mycobacterium tuberculosis infection , 2014, Front. Cell. Infect. Microbiol..

[40]  A. Price,et al.  Genome-wide association study of ancestry-specific TB risk in the South African Coloured population. , 2014, Human molecular genetics.

[41]  Domján Andrea,et al.  World Medical Association Declaration of Helsinki (WMA) - Ethical principles for medical research involving human subjects , 2014 .

[42]  R Core Team,et al.  R: A language and environment for statistical computing. , 2014 .

[43]  Christopher R. Gignoux,et al.  A Panel of Ancestry Informative Markers for the Complex Five-Way Admixed South African Coloured Population , 2013, PloS one.

[44]  Nicola J. Mulder,et al.  Determining Ancestry Proportions in Complex Admixture Scenarios in South Africa Using a Novel Proxy Ancestry Selection Method , 2013, PloS one.

[45]  E. Chan,et al.  Inhibition of Nuclear Factor-Kappa B Activation Decreases Survival of Mycobacterium tuberculosis in Human Macrophages , 2013, PloS one.

[46]  S. Hoshino,et al.  Molecular cloning and characterization of a novel isoform of the non-canonical poly(A) polymerase PAPD7. , 2013, Biochemical and biophysical research communications.

[47]  Patrick F. Sullivan,et al.  zCall: a rare variant caller for array-based genotyping: Genetics and population analysis , 2012, Bioinform..

[48]  Yusuke Nakamura,et al.  Genome-wide association studies of tuberculosis in Asians identify distinct at-risk locus for young tuberculosis , 2012, Journal of Human Genetics.

[49]  M. Fallahi-Sichani,et al.  NF-κB Signaling Dynamics Play a Key Role in Infection Control in Tuberculosis , 2012, Front. Physio..

[50]  M. Newport,et al.  Common variants at 11p13 are associated with susceptibility to tuberculosis , 2012, Nature Genetics.

[51]  John P A Ioannidis,et al.  What Should the Genome-wide Significance Threshold Be? Empirical Replication of Borderline Genetic Associations Yfor a Full List of Investigators Offering Data and Clarifications See Acknowledgments , 2022 .

[52]  Bachti Alisjahbana,et al.  A genome wide association study of pulmonary tuberculosis susceptibility in Indonesians , 2012, BMC Medical Genetics.

[53]  N. Dalgıç,et al.  Relationship between Toll-Like Receptor 8 Gene Polymorphisms and Pediatric Pulmonary Tuberculosis , 2011, Disease markers.

[54]  Timothy R Sterling,et al.  Novel human genetic variants associated with extrapulmonary tuberculosis: a pilot genome wide association study , 2011, BMC Research Notes.

[55]  Edward S. Kim,et al.  MicroRNA-related genetic variations as predictors for risk of second primary tumor and/or recurrence in patients with early-stage head and neck cancer. , 2010, Carcinogenesis.

[56]  A. Morris,et al.  Genome-wide association analyses identifies a susceptibility locus for tuberculosis on chromosome 18q11.2 , 2010, Nature Genetics.

[57]  W. Brooks.  X Chromosome Inactivation and Autoimmunity , 2010, Clinical reviews in allergy & immunology.

[58]  P. V. van Helden,et al.  Impact of age and sex on mycobacterial immunity in an area of high tuberculosis incidence. , 2010, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease.

[59]  C. Seoighe,et al.  Genome-wide analysis of the structure of the South African Coloured Population in the Western Cape , 2010, Human Genetics.

[60]  H. Ostrer,et al.  Genome-wide patterns of population structure and admixture among Hispanic/Latino populations , 2010, Proceedings of the National Academy of Sciences.

[61]  Lluis Quintana-Murci,et al.  Strong maternal Khoisan contribution to the South African coloured population: a case of gender-biased admixture. , 2010, American journal of human genetics.

[62]  M. Province,et al.  Avoiding the high Bonferroni penalty in genome‐wide association studies , 2009, Genetic epidemiology.

[63]  Stephen L. Hauser,et al.  Genome-wide patterns of population structure and admixture in West Africans and African Americans , 2009, Proceedings of the National Academy of Sciences.

[64]  T. Lawrence.  The nuclear factor NF-kappaB pathway in inflammation. , 2009, Cold Spring Harbor perspectives in biology.

[65]  David H. Alexander,et al.  Fast model-based estimation of ancestry in unrelated individuals. , 2009, Genome research.

[66]  A. Hoffmann,et al.  NF‐κB signaling , 2009, Wiley interdisciplinary reviews. Systems biology and medicine.

[67]  R. Gie,et al.  No decrease in annual risk of tuberculosis infection in endemic area in Cape Town, South Africa , 2009, Tropical medicine & international health : TM & IH.

[68]  T. Lawrence.  The Nuclear Factor NF-kB Pathway in Inflammation , 2009 .

[69]  S. Nejentsev,et al.  Genetic Association and Expression Studies Indicate a Role of Toll-Like Receptor 8 in Pulmonary Tuberculosis , 2008, PLoS genetics.

[70]  S. Tishkoff,et al.  African genetic diversity: implications for human demographic history, modern human origins, and complex disease mapping. , 2008, Annual review of genomics and human genetics.

[71]  N. Freimer,et al.  Geographic Patterns of Genome Admixture in Latin American Mestizos , 2008, PLoS genetics.

[72]  K. Taylor,et al.  Genome-Wide Association , 2007, Diabetes.

[73]  Kazuyoshi Ikuta,et al.  The RING finger ubiquitin ligase RNF125/TRAC-1 down-modulates HIV-1 replication in primary human peripheral blood mononuclear cells. , 2007, Virology.

[74]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[75]  R. Straub,et al.  Estrogens and Autoimmune Diseases , 2006, Annals of the New York Academy of Sciences.

[76]  Ravi Sachidanandam,et al.  A germline-specific class of small RNAs binds mammalian Piwi proteins , 2006, Nature.

[77]  J. Flynn,et al.  Lessons from experimental Mycobacterium tuberculosis infections. , 2006, Microbes and infection.

[78]  C. Harding,et al.  Role of Phagosomes and Major Histocompatibility Complex Class II (MHC-II) Compartment in MHC-II Antigen Processing of Mycobacterium tuberculosis in Human Macrophages , 2006, Infection and Immunity.

[79]  John L. Johnson,et al.  Mechanisms of Apoptosis of T-Cells in Human Tuberculosis , 2005, Journal of Clinical Immunology.

[80]  M. Daly,et al.  Ipr1 gene mediates innate immunity to tuberculosis , 2005, Nature.

[81]  S. Bao,et al.  The activation of Akt/PKB signaling pathway and cell survival , 2005, Journal of cellular and molecular medicine.

[82]  T. Shinka,et al.  Down-regulation of drs mRNA in human prostate carcinomas. , 2003, Human pathology.

[83]  K. Berhane,et al.  Sex-specific effects of asthma on pulmonary function in children. , 2000, American journal of respiratory and critical care medicine.

[84]  C. Greenwood,et al.  Linkage of tuberculosis to chromosome 2q35 loci, including NRAMP1, in a large aboriginal Canadian family. , 2000, American journal of human genetics.

[85]  R. Gie,et al.  Genetic susceptibility to tuberculosis in Africans: a genome-wide scan. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[86]  G. Vanham,et al.  Apoptosis and T cell hyporesponsiveness in pulmonary tuberculosis. , 1999, The Journal of infectious diseases.

[87]  P. Andersen,et al.  Genetic and environmental influences on premature death in adult adoptees. , 1988, The New England journal of medicine.

[88]  Comstock Gw.  Tuberculosis in twins: a re-analysis of the Prophit survey. , 1978, The American review of respiratory disease.

[89]  G. Comstock.  Tuberculosis in twins: a re-analysis of the Prophit survey. , 1978, The American review of respiratory disease.