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Leveraging biobank-scale rare and common variant analyses to identify ASPHD1 as the main driver of reproductive traits in the 16p11.2 locus

View ORCID ProfileKatrin Männik, Thomas Arbogast, View ORCID ProfileMaarja Lepamets, View ORCID ProfileKaido Lepik, Anna Pellaz, Herta Ademi, Zachary A Kupchinsky, View ORCID ProfileJacob Ellegood, View ORCID ProfileCatia Attanasio, Andrea Messina, View ORCID ProfileSamuel Rotman, Sandra Martin-Brevet, Estelle Dubruc, Jacqueline Chrast, Jason P Lerch, Lily R Qiu, Triin Laisk, The 16p11.2 European Consortium, The Simons VIP Consortium, The eQTLGen Consortium, View ORCID ProfileR Mark Henkelman, Sébastien Jacquemont, View ORCID ProfileYann Herault, Cecilia M Lindgren, View ORCID ProfileHedi Peterson, Jean Christophe Stehle, View ORCID ProfileNicholas Katsanis, View ORCID ProfileZoltan Kutalik, View ORCID ProfileSerge Nef, View ORCID ProfileBogdan Draganski, View ORCID ProfileErica E Davis, Reedik Mägi, View ORCID ProfileAlexandre Reymond
doi: https://doi.org/10.1101/716415
Katrin Männik
1Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
2Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
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  • For correspondence: katrin.mannik@unil.ch
Thomas Arbogast
1Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
3Center for Human Disease Modeling, Duke University Medical Center, Durham, NC, USA
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Maarja Lepamets
2Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
4Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia
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Kaido Lepik
5Institute of Computer Science, University of Tartu, Tartu, Estonia
6Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne, Switzerland
7Swiss Institute of Bioinformatics, Lausanne, Switzerland
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Anna Pellaz
1Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
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Herta Ademi
8Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland
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Zachary A Kupchinsky
3Center for Human Disease Modeling, Duke University Medical Center, Durham, NC, USA
21Washington University School of Medicine, St. Louis, MO, USA
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Jacob Ellegood
9Mouse Imaging Center, the Hospital for Sick Children, Toronto, Canada
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Catia Attanasio
1Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
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Andrea Messina
10Endocrinology, Diabetes & Metabolism Service, Lausanne University Hospital, Lausanne, Switzerland
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Samuel Rotman
11Service of Clinical Pathology, Lausanne University Hospital, Lausanne, Switzerland
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Sandra Martin-Brevet
12LREN, Department of Clinical Neuroscience, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
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Estelle Dubruc
11Service of Clinical Pathology, Lausanne University Hospital, Lausanne, Switzerland
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Jacqueline Chrast
1Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
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Jason P Lerch
9Mouse Imaging Center, the Hospital for Sick Children, Toronto, Canada
22Wellcome Centre for Integrative Neuroimaging, The University of Oxford, Oxford, UK
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Lily R Qiu
9Mouse Imaging Center, the Hospital for Sick Children, Toronto, Canada
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Triin Laisk
2Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
13Women’s Clinic, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia
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R Mark Henkelman
9Mouse Imaging Center, the Hospital for Sick Children, Toronto, Canada
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Sébastien Jacquemont
14Service of Medical Genetics, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
15CHU Sainte-Justine Research Centre, University of Montreal, Montreal, Canada
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Yann Herault
16Institute of Genetics and Molecular and Cellular Biology, Illkirch, France
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Cecilia M Lindgren
17Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
18Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
19The Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK
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Hedi Peterson
5Institute of Computer Science, University of Tartu, Tartu, Estonia
20Quretec Ltd, Tartu, Estonia
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Jean Christophe Stehle
11Service of Clinical Pathology, Lausanne University Hospital, Lausanne, Switzerland
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Nicholas Katsanis
3Center for Human Disease Modeling, Duke University Medical Center, Durham, NC, USA
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Zoltan Kutalik
6Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne, Switzerland
7Swiss Institute of Bioinformatics, Lausanne, Switzerland
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Serge Nef
8Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland
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Bogdan Draganski
12LREN, Department of Clinical Neuroscience, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
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Erica E Davis
3Center for Human Disease Modeling, Duke University Medical Center, Durham, NC, USA
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Reedik Mägi
2Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
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Alexandre Reymond
1Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
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Abstract

Whereas genome-wide association studies (GWAS) allowed identifying thousands of associations between variants and traits, their success rate in pinpointing causal genes has been disproportionately low. Here, we integrate biobank-scale phenotype data from carriers of a rare copy-number variant (CNV), Mendelian randomization and animal modeling to identify causative genes in a GWAS locus for age at menarche (AaM). We show that the dosage of the 16p11.2 BP4-BP5 interval is correlated positively with AaM in the UK and Estonian biobanks and 16p11.2 clinical cohorts, with a directionally consistent trend for pubertal onset in males. These correlations parallel an increase in reproductive tract disorders in both sexes. In support of these observations, 16p11.2 mouse models display perturbed pubertal onset and structurally altered reproductive organs that track with CNV dose. Further, we report a negative correlation between the 16p11.2 dosage and relative hypothalamic volume in both humans and mice, intimating a perturbation in the gonadotropin-releasing hormone (GnRH) axis. Two independent lines of evidence identified candidate causal genes for AaM; Mendelian randomization and agnostic dosage modulation of each 16p11.2 gene in zebrafish gnrh3:egfp models. ASPHD1, expressed predominantly in brain and pituitary gland, emerged as a major phenotype driver; and it is subject to modulation by KCTD13 to exacerbate GnRH neuron phenotype. Together, our data highlight the power of an interdisciplinary approach to elucidate disease etiologies underlying complex traits.

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Posted July 26, 2019.
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Leveraging biobank-scale rare and common variant analyses to identify ASPHD1 as the main driver of reproductive traits in the 16p11.2 locus
Katrin Männik, Thomas Arbogast, Maarja Lepamets, Kaido Lepik, Anna Pellaz, Herta Ademi, Zachary A Kupchinsky, Jacob Ellegood, Catia Attanasio, Andrea Messina, Samuel Rotman, Sandra Martin-Brevet, Estelle Dubruc, Jacqueline Chrast, Jason P Lerch, Lily R Qiu, Triin Laisk, The 16p11.2 European Consortium, The Simons VIP Consortium, The eQTLGen Consortium, R Mark Henkelman, Sébastien Jacquemont, Yann Herault, Cecilia M Lindgren, Hedi Peterson, Jean Christophe Stehle, Nicholas Katsanis, Zoltan Kutalik, Serge Nef, Bogdan Draganski, Erica E Davis, Reedik Mägi, Alexandre Reymond
bioRxiv 716415; doi: https://doi.org/10.1101/716415
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Leveraging biobank-scale rare and common variant analyses to identify ASPHD1 as the main driver of reproductive traits in the 16p11.2 locus
Katrin Männik, Thomas Arbogast, Maarja Lepamets, Kaido Lepik, Anna Pellaz, Herta Ademi, Zachary A Kupchinsky, Jacob Ellegood, Catia Attanasio, Andrea Messina, Samuel Rotman, Sandra Martin-Brevet, Estelle Dubruc, Jacqueline Chrast, Jason P Lerch, Lily R Qiu, Triin Laisk, The 16p11.2 European Consortium, The Simons VIP Consortium, The eQTLGen Consortium, R Mark Henkelman, Sébastien Jacquemont, Yann Herault, Cecilia M Lindgren, Hedi Peterson, Jean Christophe Stehle, Nicholas Katsanis, Zoltan Kutalik, Serge Nef, Bogdan Draganski, Erica E Davis, Reedik Mägi, Alexandre Reymond
bioRxiv 716415; doi: https://doi.org/10.1101/716415

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