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Human knockouts in a cohort with a high rate of consanguinity

Danesh Saleheen, View ORCID ProfilePradeep Natarajan, View ORCID ProfileWei Zhao, View ORCID ProfileAsif Rasheed, View ORCID ProfileSumeet Khetarpal, View ORCID ProfileHong-Hee Won, View ORCID ProfileKonrad J. Karczewski, View ORCID ProfileAnne H O’Donnell-Luria, View ORCID ProfileKaitlin E. Samocha, View ORCID ProfileNamrata Gupta, View ORCID ProfileMozzam Zaidi, View ORCID ProfileMaria Samuel, View ORCID ProfileAtif Imran, View ORCID ProfileShahid Abbas, View ORCID ProfileFaisal Majeed, View ORCID ProfileMadiha Ishaq, View ORCID ProfileSaba Akhtar, View ORCID ProfileKevin Trindade, View ORCID ProfileMegan Mucksavage, View ORCID ProfileNadeem Qamar, View ORCID ProfileKhan Shah Zaman, View ORCID ProfileZia Yaqoob, View ORCID ProfileTahir Saghir, View ORCID ProfileSyed Nadeem Hasan Rizvi, View ORCID ProfileAnis Memon, View ORCID ProfileNadeem Hayyat Mallick, View ORCID ProfileMohammad Ishaq, View ORCID ProfileSyed Zahed Rasheed, View ORCID ProfileFazal-ur-Rehman Memon, View ORCID ProfileKhalid Mahmood, View ORCID ProfileNaveeduddin Ahmed, View ORCID ProfileRon Do, View ORCID ProfileDaniel G. MacArthur, View ORCID ProfileStacey Gabriel, View ORCID ProfileEric S. Lander, View ORCID ProfileMark J. Daly, View ORCID ProfilePhilippe Frossard, View ORCID ProfileJohn Danesh, View ORCID ProfileDaniel J. Rader, View ORCID ProfileSekar Kathiresan
doi: https://doi.org/10.1101/031518
Danesh Saleheen
1Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
2Center for Non-Communicable Diseases, Karachi, Pakistan
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  • For correspondence: saleheen@mail.med.upenn.edu sekar@broadinstitute.org
Pradeep Natarajan
3Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
4Broad Institute of Harvard and MIT, Cambridge, MA, USA
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Wei Zhao
1Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
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Asif Rasheed
2Center for Non-Communicable Diseases, Karachi, Pakistan
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Sumeet Khetarpal
5Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
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Hong-Hee Won
3Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
4Broad Institute of Harvard and MIT, Cambridge, MA, USA
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Konrad J. Karczewski
4Broad Institute of Harvard and MIT, Cambridge, MA, USA
6Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA
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Anne H O’Donnell-Luria
4Broad Institute of Harvard and MIT, Cambridge, MA, USA
6Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA
7Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, USA
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Kaitlin E. Samocha
6Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA
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Namrata Gupta
4Broad Institute of Harvard and MIT, Cambridge, MA, USA
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Mozzam Zaidi
2Center for Non-Communicable Diseases, Karachi, Pakistan
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Maria Samuel
2Center for Non-Communicable Diseases, Karachi, Pakistan
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Atif Imran
2Center for Non-Communicable Diseases, Karachi, Pakistan
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Shahid Abbas
8Faisalabad Institute of Cardiology, Faisalabad, Pakistan
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Faisal Majeed
2Center for Non-Communicable Diseases, Karachi, Pakistan
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Madiha Ishaq
2Center for Non-Communicable Diseases, Karachi, Pakistan
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Saba Akhtar
2Center for Non-Communicable Diseases, Karachi, Pakistan
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Kevin Trindade
5Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
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Megan Mucksavage
5Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
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Nadeem Qamar
9National Institute of Cardiovascular Disorders, Karachi, Pakistan
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Khan Shah Zaman
9National Institute of Cardiovascular Disorders, Karachi, Pakistan
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Zia Yaqoob
9National Institute of Cardiovascular Disorders, Karachi, Pakistan
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Tahir Saghir
9National Institute of Cardiovascular Disorders, Karachi, Pakistan
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Syed Nadeem Hasan Rizvi
9National Institute of Cardiovascular Disorders, Karachi, Pakistan
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Anis Memon
9National Institute of Cardiovascular Disorders, Karachi, Pakistan
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Nadeem Hayyat Mallick
10Punjab Institute of Cardiology, Lahore, Pakistan
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Mohammad Ishaq
11Karachi Institute of Heart Diseases, Karachi, Pakistan
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Syed Zahed Rasheed
11Karachi Institute of Heart Diseases, Karachi, Pakistan
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Fazal-ur-Rehman Memon
12Red Crescent Institute of Cardiology, Hyderabad, Pakistan
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Khalid Mahmood
13The Civil Hospital, Karachi, Pakistan
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Naveeduddin Ahmed
14Liaquat National Hospital, Karachi, Pakistan
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Ron Do
15Department of Genetics and Genomic Sciences, Mount Sinai Medical Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
16The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Daniel G. MacArthur
4Broad Institute of Harvard and MIT, Cambridge, MA, USA
6Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA
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Stacey Gabriel
4Broad Institute of Harvard and MIT, Cambridge, MA, USA
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Eric S. Lander
4Broad Institute of Harvard and MIT, Cambridge, MA, USA
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Mark J. Daly
4Broad Institute of Harvard and MIT, Cambridge, MA, USA
6Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA
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Philippe Frossard
2Center for Non-Communicable Diseases, Karachi, Pakistan
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John Danesh
17Department of Public Health and Primary Care, University of Cambridge, UK
18Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK
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Daniel J. Rader
5Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
19Department of Human Genetics, University of Pennsylvania, USA
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Sekar Kathiresan
3Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
4Broad Institute of Harvard and MIT, Cambridge, MA, USA
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  • For correspondence: saleheen@mail.med.upenn.edu sekar@broadinstitute.org
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Summary

A major goal of biomedicine is to understand the function of every gene in the human genome.1 Null mutations can disrupt both copies of a given gene in humans and phenotypic analysis of such ‘human knockouts’ can provide insight into gene function. To date, comprehensive analysis of genes knocked out in humans has been limited by the fact that null mutations are infrequent in the general population and so, observing an individual homozygous null for a given gene is exceedingly rare.2,3 However, consanguineous unions are more likely to result in offspring who carry homozygous null mutations. In Pakistan, consanguinity rates are notably high.4 Here, we sequenced the protein-coding regions of 7,078 adult participants living in Pakistan and performed phenotypic analysis to identify homozygous null individuals and to understand consequences of complete gene disruption in humans. We enumerated 36,850 rare (<1 % minor allele frequency) null mutations. These homozygous null mutations led to complete inactivation of 961 genes in at least one participant. Homozygosity for null mutations at APOC3 was associated with absent plasma apolipoprotein C-III levels; at PLAG27, with absent enzymatic activity of soluble lipoprotein-associated phospholipase A2; at CYP2F1, with higher plasma interleukin-8 concentrations; and at either A3GALT2 or NRG4, with markedly reduced plasma insulin C-peptide concentrations. After physiologic challenge with oral fat, APOC3 knockouts displayed marked blunting of the usual post-prandial rise in plasma triglycerides compared to wild-type family members. These observations provide a roadmap to understand the consequences of complete disruption of a large fraction of genes in the human genome.

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Posted November 12, 2015.
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Human knockouts in a cohort with a high rate of consanguinity
Danesh Saleheen, Pradeep Natarajan, Wei Zhao, Asif Rasheed, Sumeet Khetarpal, Hong-Hee Won, Konrad J. Karczewski, Anne H O’Donnell-Luria, Kaitlin E. Samocha, Namrata Gupta, Mozzam Zaidi, Maria Samuel, Atif Imran, Shahid Abbas, Faisal Majeed, Madiha Ishaq, Saba Akhtar, Kevin Trindade, Megan Mucksavage, Nadeem Qamar, Khan Shah Zaman, Zia Yaqoob, Tahir Saghir, Syed Nadeem Hasan Rizvi, Anis Memon, Nadeem Hayyat Mallick, Mohammad Ishaq, Syed Zahed Rasheed, Fazal-ur-Rehman Memon, Khalid Mahmood, Naveeduddin Ahmed, Ron Do, Daniel G. MacArthur, Stacey Gabriel, Eric S. Lander, Mark J. Daly, Philippe Frossard, John Danesh, Daniel J. Rader, Sekar Kathiresan
bioRxiv 031518; doi: https://doi.org/10.1101/031518
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Human knockouts in a cohort with a high rate of consanguinity
Danesh Saleheen, Pradeep Natarajan, Wei Zhao, Asif Rasheed, Sumeet Khetarpal, Hong-Hee Won, Konrad J. Karczewski, Anne H O’Donnell-Luria, Kaitlin E. Samocha, Namrata Gupta, Mozzam Zaidi, Maria Samuel, Atif Imran, Shahid Abbas, Faisal Majeed, Madiha Ishaq, Saba Akhtar, Kevin Trindade, Megan Mucksavage, Nadeem Qamar, Khan Shah Zaman, Zia Yaqoob, Tahir Saghir, Syed Nadeem Hasan Rizvi, Anis Memon, Nadeem Hayyat Mallick, Mohammad Ishaq, Syed Zahed Rasheed, Fazal-ur-Rehman Memon, Khalid Mahmood, Naveeduddin Ahmed, Ron Do, Daniel G. MacArthur, Stacey Gabriel, Eric S. Lander, Mark J. Daly, Philippe Frossard, John Danesh, Daniel J. Rader, Sekar Kathiresan
bioRxiv 031518; doi: https://doi.org/10.1101/031518

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