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ResearchIn-Press PreviewEndocrinologyMetabolismReproductive biology Open Access | 10.1172/JCI198215

Systems genetics approaches model the heritable architecture of polyendocrine metabolic ovarian syndrome

Christy M. Nguyen,1 Leandro M. Velez,1 Youngseo Cheon,1 Cimone L. Jackson,1 Casey D. Johnson,1 Ian Tamburini,1 Mingqi Zhou,1 Erik Alvstad,1 Isoo Yoon,1 Farheen Dustagheer,1 Marie Li,1 Tvisha Gujjarlapudi,1 Kaitlene Ofilan,1 Neha Mishra,1 Evan G. Williams,2 Danica Kwan,1 Carlos H. Viesi,1 Naveena Ujagar,3 David G. Ashbrook,4 Alistair Senior,5 Marin E. Nelson,5 Nicholas R. Pannunzio,1 Selma Masri,1 Evgeny Kvon,6 Grant MacGregor,6 Cholsoon Jang,1 Vittorio Sebastiano,1 Minji Byun,7 Changrui Xiao,8 Alexander S. Kauffman,9 Robert W. Williams,10 David E. James,5 Ivan Marazzi,1 Dequina Nicholas,11 and Marcus Seldin1

1Department of Biological Chemistry, University of California, Irvine, Irvine, United States of America

2Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belval, Luxembourg

3Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

4Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh, United States of America

5School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia

6Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

7Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, United States of America

8Department of Neurology, University of California, Irvine, Irvine, United States of America

9Department of OBGYN and Reproductive Sciences, University of California, San Diego, La Jolla, United States of America

10Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, United States of America

11Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, United States of America

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1Department of Biological Chemistry, University of California, Irvine, Irvine, United States of America

2Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belval, Luxembourg

3Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

4Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh, United States of America

5School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia

6Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

7Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, United States of America

8Department of Neurology, University of California, Irvine, Irvine, United States of America

9Department of OBGYN and Reproductive Sciences, University of California, San Diego, La Jolla, United States of America

10Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, United States of America

11Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, United States of America

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1Department of Biological Chemistry, University of California, Irvine, Irvine, United States of America

2Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belval, Luxembourg

3Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

4Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh, United States of America

5School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia

6Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

7Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, United States of America

8Department of Neurology, University of California, Irvine, Irvine, United States of America

9Department of OBGYN and Reproductive Sciences, University of California, San Diego, La Jolla, United States of America

10Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, United States of America

11Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, United States of America

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1Department of Biological Chemistry, University of California, Irvine, Irvine, United States of America

2Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belval, Luxembourg

3Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

4Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh, United States of America

5School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia

6Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

7Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, United States of America

8Department of Neurology, University of California, Irvine, Irvine, United States of America

9Department of OBGYN and Reproductive Sciences, University of California, San Diego, La Jolla, United States of America

10Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, United States of America

11Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, United States of America

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1Department of Biological Chemistry, University of California, Irvine, Irvine, United States of America

2Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belval, Luxembourg

3Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

4Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh, United States of America

5School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia

6Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

7Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, United States of America

8Department of Neurology, University of California, Irvine, Irvine, United States of America

9Department of OBGYN and Reproductive Sciences, University of California, San Diego, La Jolla, United States of America

10Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, United States of America

11Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, United States of America

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1Department of Biological Chemistry, University of California, Irvine, Irvine, United States of America

2Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belval, Luxembourg

3Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

4Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh, United States of America

5School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia

6Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

7Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, United States of America

8Department of Neurology, University of California, Irvine, Irvine, United States of America

9Department of OBGYN and Reproductive Sciences, University of California, San Diego, La Jolla, United States of America

10Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, United States of America

11Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, United States of America

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1Department of Biological Chemistry, University of California, Irvine, Irvine, United States of America

2Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belval, Luxembourg

3Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

4Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh, United States of America

5School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia

6Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

7Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, United States of America

8Department of Neurology, University of California, Irvine, Irvine, United States of America

9Department of OBGYN and Reproductive Sciences, University of California, San Diego, La Jolla, United States of America

10Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, United States of America

11Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, United States of America

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1Department of Biological Chemistry, University of California, Irvine, Irvine, United States of America

2Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belval, Luxembourg

3Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

4Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh, United States of America

5School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia

6Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

7Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, United States of America

8Department of Neurology, University of California, Irvine, Irvine, United States of America

9Department of OBGYN and Reproductive Sciences, University of California, San Diego, La Jolla, United States of America

10Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, United States of America

11Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, United States of America

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1Department of Biological Chemistry, University of California, Irvine, Irvine, United States of America

2Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belval, Luxembourg

3Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

4Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh, United States of America

5School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia

6Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

7Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, United States of America

8Department of Neurology, University of California, Irvine, Irvine, United States of America

9Department of OBGYN and Reproductive Sciences, University of California, San Diego, La Jolla, United States of America

10Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, United States of America

11Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, United States of America

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1Department of Biological Chemistry, University of California, Irvine, Irvine, United States of America

2Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belval, Luxembourg

3Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

4Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh, United States of America

5School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia

6Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

7Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, United States of America

8Department of Neurology, University of California, Irvine, Irvine, United States of America

9Department of OBGYN and Reproductive Sciences, University of California, San Diego, La Jolla, United States of America

10Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, United States of America

11Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, United States of America

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1Department of Biological Chemistry, University of California, Irvine, Irvine, United States of America

2Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belval, Luxembourg

3Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

4Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh, United States of America

5School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia

6Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

7Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, United States of America

8Department of Neurology, University of California, Irvine, Irvine, United States of America

9Department of OBGYN and Reproductive Sciences, University of California, San Diego, La Jolla, United States of America

10Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, United States of America

11Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, United States of America

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1Department of Biological Chemistry, University of California, Irvine, Irvine, United States of America

2Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belval, Luxembourg

3Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

4Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh, United States of America

5School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia

6Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

7Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, United States of America

8Department of Neurology, University of California, Irvine, Irvine, United States of America

9Department of OBGYN and Reproductive Sciences, University of California, San Diego, La Jolla, United States of America

10Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, United States of America

11Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, United States of America

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1Department of Biological Chemistry, University of California, Irvine, Irvine, United States of America

2Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belval, Luxembourg

3Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

4Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh, United States of America

5School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia

6Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

7Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, United States of America

8Department of Neurology, University of California, Irvine, Irvine, United States of America

9Department of OBGYN and Reproductive Sciences, University of California, San Diego, La Jolla, United States of America

10Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, United States of America

11Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, United States of America

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1Department of Biological Chemistry, University of California, Irvine, Irvine, United States of America

2Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belval, Luxembourg

3Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

4Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh, United States of America

5School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia

6Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

7Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, United States of America

8Department of Neurology, University of California, Irvine, Irvine, United States of America

9Department of OBGYN and Reproductive Sciences, University of California, San Diego, La Jolla, United States of America

10Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, United States of America

11Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, United States of America

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1Department of Biological Chemistry, University of California, Irvine, Irvine, United States of America

2Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belval, Luxembourg

3Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

4Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh, United States of America

5School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia

6Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

7Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, United States of America

8Department of Neurology, University of California, Irvine, Irvine, United States of America

9Department of OBGYN and Reproductive Sciences, University of California, San Diego, La Jolla, United States of America

10Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, United States of America

11Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, United States of America

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1Department of Biological Chemistry, University of California, Irvine, Irvine, United States of America

2Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belval, Luxembourg

3Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

4Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh, United States of America

5School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia

6Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

7Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, United States of America

8Department of Neurology, University of California, Irvine, Irvine, United States of America

9Department of OBGYN and Reproductive Sciences, University of California, San Diego, La Jolla, United States of America

10Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, United States of America

11Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, United States of America

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1Department of Biological Chemistry, University of California, Irvine, Irvine, United States of America

2Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belval, Luxembourg

3Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

4Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh, United States of America

5School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia

6Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

7Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, United States of America

8Department of Neurology, University of California, Irvine, Irvine, United States of America

9Department of OBGYN and Reproductive Sciences, University of California, San Diego, La Jolla, United States of America

10Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, United States of America

11Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, United States of America

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1Department of Biological Chemistry, University of California, Irvine, Irvine, United States of America

2Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belval, Luxembourg

3Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

4Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh, United States of America

5School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia

6Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

7Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, United States of America

8Department of Neurology, University of California, Irvine, Irvine, United States of America

9Department of OBGYN and Reproductive Sciences, University of California, San Diego, La Jolla, United States of America

10Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, United States of America

11Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, United States of America

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1Department of Biological Chemistry, University of California, Irvine, Irvine, United States of America

2Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belval, Luxembourg

3Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

4Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh, United States of America

5School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia

6Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

7Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, United States of America

8Department of Neurology, University of California, Irvine, Irvine, United States of America

9Department of OBGYN and Reproductive Sciences, University of California, San Diego, La Jolla, United States of America

10Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, United States of America

11Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, United States of America

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1Department of Biological Chemistry, University of California, Irvine, Irvine, United States of America

2Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belval, Luxembourg

3Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

4Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh, United States of America

5School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia

6Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

7Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, United States of America

8Department of Neurology, University of California, Irvine, Irvine, United States of America

9Department of OBGYN and Reproductive Sciences, University of California, San Diego, La Jolla, United States of America

10Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, United States of America

11Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, United States of America

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1Department of Biological Chemistry, University of California, Irvine, Irvine, United States of America

2Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belval, Luxembourg

3Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

4Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh, United States of America

5School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia

6Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

7Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, United States of America

8Department of Neurology, University of California, Irvine, Irvine, United States of America

9Department of OBGYN and Reproductive Sciences, University of California, San Diego, La Jolla, United States of America

10Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, United States of America

11Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, United States of America

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1Department of Biological Chemistry, University of California, Irvine, Irvine, United States of America

2Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belval, Luxembourg

3Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

4Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh, United States of America

5School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia

6Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

7Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, United States of America

8Department of Neurology, University of California, Irvine, Irvine, United States of America

9Department of OBGYN and Reproductive Sciences, University of California, San Diego, La Jolla, United States of America

10Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, United States of America

11Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, United States of America

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1Department of Biological Chemistry, University of California, Irvine, Irvine, United States of America

2Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belval, Luxembourg

3Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

4Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh, United States of America

5School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia

6Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

7Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, United States of America

8Department of Neurology, University of California, Irvine, Irvine, United States of America

9Department of OBGYN and Reproductive Sciences, University of California, San Diego, La Jolla, United States of America

10Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, United States of America

11Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, United States of America

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1Department of Biological Chemistry, University of California, Irvine, Irvine, United States of America

2Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belval, Luxembourg

3Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

4Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh, United States of America

5School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia

6Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

7Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, United States of America

8Department of Neurology, University of California, Irvine, Irvine, United States of America

9Department of OBGYN and Reproductive Sciences, University of California, San Diego, La Jolla, United States of America

10Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, United States of America

11Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, United States of America

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1Department of Biological Chemistry, University of California, Irvine, Irvine, United States of America

2Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belval, Luxembourg

3Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

4Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh, United States of America

5School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia

6Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

7Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, United States of America

8Department of Neurology, University of California, Irvine, Irvine, United States of America

9Department of OBGYN and Reproductive Sciences, University of California, San Diego, La Jolla, United States of America

10Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, United States of America

11Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, United States of America

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1Department of Biological Chemistry, University of California, Irvine, Irvine, United States of America

2Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belval, Luxembourg

3Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

4Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh, United States of America

5School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia

6Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

7Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, United States of America

8Department of Neurology, University of California, Irvine, Irvine, United States of America

9Department of OBGYN and Reproductive Sciences, University of California, San Diego, La Jolla, United States of America

10Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, United States of America

11Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, United States of America

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1Department of Biological Chemistry, University of California, Irvine, Irvine, United States of America

2Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belval, Luxembourg

3Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

4Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh, United States of America

5School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia

6Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

7Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, United States of America

8Department of Neurology, University of California, Irvine, Irvine, United States of America

9Department of OBGYN and Reproductive Sciences, University of California, San Diego, La Jolla, United States of America

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2Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belval, Luxembourg

3Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

4Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh, United States of America

5School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia

6Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

7Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, United States of America

8Department of Neurology, University of California, Irvine, Irvine, United States of America

9Department of OBGYN and Reproductive Sciences, University of California, San Diego, La Jolla, United States of America

10Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, United States of America

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3Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

4Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh, United States of America

5School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia

6Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

7Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, United States of America

8Department of Neurology, University of California, Irvine, Irvine, United States of America

9Department of OBGYN and Reproductive Sciences, University of California, San Diego, La Jolla, United States of America

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1Department of Biological Chemistry, University of California, Irvine, Irvine, United States of America

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3Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

4Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh, United States of America

5School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia

6Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

7Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, United States of America

8Department of Neurology, University of California, Irvine, Irvine, United States of America

9Department of OBGYN and Reproductive Sciences, University of California, San Diego, La Jolla, United States of America

10Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, United States of America

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4Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh, United States of America

5School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia

6Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

7Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, United States of America

8Department of Neurology, University of California, Irvine, Irvine, United States of America

9Department of OBGYN and Reproductive Sciences, University of California, San Diego, La Jolla, United States of America

10Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, United States of America

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3Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

4Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh, United States of America

5School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia

6Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

7Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, United States of America

8Department of Neurology, University of California, Irvine, Irvine, United States of America

9Department of OBGYN and Reproductive Sciences, University of California, San Diego, La Jolla, United States of America

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3Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

4Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh, United States of America

5School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia

6Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

7Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, United States of America

8Department of Neurology, University of California, Irvine, Irvine, United States of America

9Department of OBGYN and Reproductive Sciences, University of California, San Diego, La Jolla, United States of America

10Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, United States of America

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3Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

4Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh, United States of America

5School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia

6Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

7Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, United States of America

8Department of Neurology, University of California, Irvine, Irvine, United States of America

9Department of OBGYN and Reproductive Sciences, University of California, San Diego, La Jolla, United States of America

10Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, United States of America

11Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, United States of America

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3Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

4Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh, United States of America

5School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia

6Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, United States of America

7Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, United States of America

8Department of Neurology, University of California, Irvine, Irvine, United States of America

9Department of OBGYN and Reproductive Sciences, University of California, San Diego, La Jolla, United States of America

10Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, United States of America

11Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, United States of America

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Published August 6, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI198215.
Copyright © 2026, Nguyen et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published August 6, 2026 - Version history
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Abstract

Polyendocrine metabolic ovarian syndrome (PMOS), formerly known as polycystic ovary syndrome (PCOS), is the most common endocrine disorder in women and is closely associated with complex diseases such as cardiovascular disease and type 2 diabetes. However, the mechanistic links between PMOS and its comorbidities remain poorly understood. Here, we present an integrative systems genetics platform that leverages genetic diversity in both mice and humans to dissect the drivers of PMOS and its associated complications. This framework uncovers conserved genetic and environmental factors underlying PMOS, identifies susceptible cell types and organs, and elucidates mechanisms linking PMOS to subsequent pathologies. For instance, we show that increased ovarian area contributes to both PMOS susceptibility and ovarian cancer progression, while specific ovary–heart signaling circuits modulate cardiac function with aging. We further identify ovarian SF3B1-mediated alternative splicing as a key mechanistic link between PMOS and metabolic traits. Pharmacologic inhibition of SF3B1 in mice reduced circulating testosterone, insulin and glucose levels, as well as fat mass expansion. Transcriptomics analysis of ovaries from mice and experiments using human cell lines localized these effects to exon skipping events in granulosa cells. Together, this study offers a mechanistic framework for modeling the diversity of PMOS pathologies and uncovers SF3B1-mediated splicing as a link between ovary function and systemic metabolism.

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