The genetic architecture of sporadic and multiple consecutive miscarriage,Nature Communications

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The genetic architecture of sporadic and multiple consecutive miscarriage
Nature Communications ( IF 14.7 ) Pub Date : 2020-11-25 , DOI: 10.1038/s41467-020-19742-5
Triin Laisk _{1,

2,

3} , Ana Luiza G Soares _{4,

5} , Teresa Ferreira ₆ , Jodie N Painter ₇ , Jenny C Censin _{6,

8} , Samantha Laber _{6,

8} , Jonas Bacelis ₉ , Chia-Yen Chen _{10,

11,

12} , Maarja Lepamets _{2,

13} , Kuang Lin ₁₄ , Siyang Liu _{15,

16} , Iona Y Millwood _{14,

17} , Avinash Ramu ₁₈ , Jennifer Southcombe ₁₉ , Marianne S Andersen ₂₀ , Ling Yang _{14,

17} , Christian M Becker ₁₉ , Anders D Børglum _{21,

22,

23} , Scott D Gordon ₇ , Jonas Bybjerg-Grauholm _{21,

24} , Øyvind Helgeland _{25,

26} , David M Hougaard _{21,

24} , Xin Jin _{15,

27} , Stefan Johansson _{26,

28} , Julius Juodakis ₂₉ , Christiana Kartsonaki _{14,

17} , Viktorija Kukushkina _{2,

13} , Penelope A Lind ₇ , Andres Metspalu ₂ , Grant W Montgomery ₃₀ , Andrew P Morris _{2,

8,

31} , Ole Mors _{21,

32} , Preben B Mortensen _{21,

33} , Pål R Njølstad _{26,

34} , Merete Nordentoft _{21,

35} , Dale R Nyholt ₃₆ , Margaret Lippincott ₃₇ , Stephanie Seminara ₃₇ , Andres Salumets _{1,

3,

38,

39} , Harold Snieder ₄₀ , Krina Zondervan _{8,

19} , Thomas Werge _{21,

41,

42} , Zhengming Chen ₁₄ , Donald F Conrad ₁₈ , Bo Jacobsson _{9,

25} , Liming Li ₄₃ , Nicholas G Martin ₇ , Benjamin M Neale _{10,

11,

12} , Rasmus Nielsen _{44,

45} , Robin G Walters _{14,

17} , Ingrid Granne ₁₉ , Sarah E Medland ₇ , Reedik Mägi ₂ , Deborah A Lawlor _{4,

5,

46} , Cecilia M Lindgren _{6,

8,

47}

Affiliation

Department of Obstetrics and Gynecology, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.
Competence Centre on Health Technologies, Tartu, Estonia.
MRC Integrated Epidemiology Unit at the University of Bristol, Bristol, UK.
Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
Big Data Institute, Li Ka Shing Center for Health for Health Information and Discovery, Oxford University, Oxford, UK.
QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
Department of Obstetrics and Gynecology, Sahlgrenska University Hospital Östra, Gothenburg, Sweden.
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK.
BGI-Shenzhen, Shenzhen, 518083, Guangdong, China.
Bioinformatics Centre, Department of Biology, University of Copenhagen, 2200, Copenhagen, Denmark.
Medical Research Council Population Health Research Unit (PHRU), University of Oxford, Oxford, UK.
Department of Genetics, Washington University in St. Louis, Saint Louis, MO, USA.
Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, UK.
Department of Endocrinology, Odense University Hospital, Odense, Denmark.
iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark.
Department of Biomedicine and Center for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.
Center for Genomics and Personalized Medicine, Aarhus University and University Hospital, Aarhus, Denmark.
Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
Department of Genetics and Bioinformatics, Health Data and Digitalisation, Norwegian Institute of Public Health, Oslo, Norway.
KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, N-5020, Bergen, Norway.
School of Medicine, South China University of Technology, Guangzhou, 510006, Guangdong, China.
Department of Medical Genetics, Haukeland University Hospital, N-5021, Bergen, Norway.
Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
University of Queensland, St Lucia, QLD, Australia.
Department of Biostatistics, University of Liverpool, Liverpool, UK.
Psychosis Research Unit, Aarhus University Hospital - Psychiatry, Aarhus, Denmark.
National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark.
Department of Pediatrics, Haukeland University Hospital, Bergen, Norway.
Copenhagen University Hospital, Mental Health Center Copenhagen, Mental Health Services in the Capital Region of Denmark, Copenhagen, Denmark.
School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia.
Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, MA, USA.
Institute of Bio- and Translational Medicine, University of Tartu, Tartu, Estonia.
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark.
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
Department of Epidemiology & Biostatistics, Peking University Health Science Centre, Peking University, Beijing, China.
Department of Integrative Biology, University of California Berkeley, Berkeley, CA, USA.
Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, Copenhagen, Denmark.
Bristol National Institute of Health Research Biomedical Research Centre, Bristol, UK.
Program in Medical and Population Genetics, Broad Institute, Boston, MA, USA.

Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P = 3.2 × 10⁻⁸, odds ratio (OR) = 1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF = 6.4%, P = 1.3 × 10⁻⁸, OR = 1.7; rs143445068, MAF = 0.8%, P = 5.2 × 10⁻⁹, OR = 3.4; rs183453668, MAF = 0.5%, P = 2.8 × 10⁻⁸, OR = 3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.

中文翻译：

偶发性和多次连续流产的遗传结构

流产是一种常见且复杂的特征，影响约 15% 的临床确诊妊娠。在这里，我们展示了大规模遗传关联分析的结果，其中包括来自五个不同血统的 69,054 例散发性流产病例、750 例欧洲血统的多次（≥3）连续流产病例以及多达 359,469 名女性对照。我们在欧洲血统荟萃分析和三个基因组中发现了一个与散发性流产有关的全基因组显着关联（rs146350366，次要等位基因频率（MAF）1.2%， P = 3.2 × 10 ^-8 ，比值比（OR）= 1.4）与多次连续流产有广泛的显着相关性（rs7859844，MAF = 6.4%， P = 1.3 × 10 ⁻⁸ ，OR = 1.7；rs143445068，MAF = 0.8%， P = 5.2 × 10 ⁻⁹ ，OR = 3.4；rs183453668，MAF = 0.5%， P = 2.8 × 10 ^-8 ，OR = 3.8）。我们通过生物库规模的孟德尔随机化、遗传力和遗传相关分析进一步研究流产的遗传结构。我们的结果表明，流产的发病机制部分是由与胎盘生物学潜在相关的遗传变异驱动的，并说明了大规模生物库数据对于理解这种妊娠并发症的效用。

更新日期：2020-11-26

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