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Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity
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Abstract
A major goal of biomedicine is to understand the function of every gene in the human genome. Loss-of-function mutations can disrupt both copies of a given gene in humans and phenotypic analysis of such 'human knockouts' can provide insight into gene function. Consanguineous unions are more likely to result in offspring carrying homozygous loss-of-function mutations. In Pakistan, consanguinity rates are notably high. Here we sequence the protein-coding regions of 10,503 adult participants in the Pakistan Risk of Myocardial Infarction Study (PROMIS), designed to understand the determinants of cardiometabolic diseases in individuals from South Asia. We identified individuals carrying homozygous predicted loss-of-function (pLoF) mutations, and performed phenotypic analysis involving more than 200 biochemical and disease traits. We enumerated 49,138 rare (<1% minor allele frequency) pLoF mutations. These pLoF mutations are estimated to knock out 1,317 genes, each in at least one participant. Homozygosity for pLoF mutations at PLA2G7 was associated with absent enzymatic activity of soluble lipoprotein-associated phospholipase A2; at CYP2F1, with higher plasma interleukin-8 concentrations; at TREH, with lower concentrations of apoB-containing lipoprotein subfractions; at either A3GALT2 or NRG4, with markedly reduced plasma insulin C-peptide concentrations; and at SLC9A3R1, with mediators of calcium and phosphate signalling. Heterozygous deficiency of APOC3 has been shown to protect against coronary heart disease; we identified APOC3 homozygous pLoF carriers in our cohort. We recruited these human knockouts and challenged them with an oral fat load. Compared with family members lacking the mutation, individuals with APOC3 knocked out displayed marked blunting of the usual post-prandial rise in plasma triglycerides. Overall, these observations provide a roadmap for a 'human knockout project', a systematic effort to understand the phenotypic consequences of complete disruption of genes in humans.
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“Furthermore, individuals who are homozygous for APOC3 LOF variants have very-low-fasting TG levels, with no rise after a fat load.9”
From Clinical review on triglycerides (2020) · cites this paper as [9]
In the citing paper
“Some rare heterozygous loss-of-function (LOF) variants are associated with reduced TG levels. These patients show protection from ASCVD providing important evidence for a causal role of TG for ASCVD.”
From Clinical review on triglycerides (2020) · cites this paper as [9]
In the citing paper
“For instance, rare heterozygous LOF variants in APOC3 encoding apo C-III are associated with ∼50% reduced TG levels and significantly increased clearance of very-low-density lipoprotein (VLDL).8,9”
From Clinical review on triglycerides (2020) · cites this paper as [9]
In the citing paper
“and is a genetically validated target to reduce ASCVD risk.8–10,64–66”
From Clinical review on triglycerides (2020) · cites this paper as [9]
In the citing paper
“In addition, studies in populations with high rates of consanguinity make it possible to identify individuals homozygous for otherwise rare loss-of-function alleles, the basis for a ‘human knockout’ project to systematically investigate the phenotypic consequences of gene disruption in humans53,54.”
From A brief history of human disease genetics (2020) · cites this paper as [54]
In the citing paper
“Efforts to probe the clinical consequences of coding alleles with large phenotypic effects (particularly null alleles) in humans53,54 and across diverse animal models116 represent powerful strategies for extending functional analyses to the whole-body level.”
From A brief history of human disease genetics (2020) · cites this paper as [54]
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Metadata
- Authors
- Saleheen, D., Natarajan, P., Armean, I. M., Zhao, W., Rasheed, A., Khetarpal, S. A., Won, H.-H., Karczewski, K. J., O’Donnell-Luria, A. H., Samocha, K. E., Weisburd, B., Gupta, N., Zaidi, M., Samuel, M., Imran, A., Abbas, S., Majeed, F., Ishaq, M., Akhtar, S., Trindade, K., Mucksavage, M., Qamar, N., Zaman, K. S., Yaqoob, Z., Saghir, T., Rizvi, S. N. H., Memon, A., Hayyat Mallick, N., Ishaq, M., Rasheed, S. Z., Memon, F.-U.-R., Mahmood, K., Ahmed, N., Do, R., Krauss, R. M., MacArthur, D. G., Gabriel, S., Lander, E. S., Daly, M. J., Frossard, P., Danesh, J., Rader, D. J., & Kathiresan, S.
- Affiliations
- Center for Non-Communicable Diseases (PK)
- Broad Institute (US)
- University of Pennsylvania (US)
- Samsung Medical Center (KR)
- Karachi Institute of Heart Diseases (PK)
- National Institute of Cardiovascular Diseases (PK)
- Civil Hospital Karachi (PK)
- Liaquat National Hospital (PK)
- Icahn School of Medicine at Mount Sinai (US)
- University of Cambridge (GB)
- Corresponding author
- Saleheen, Danish
- Kathiresan, Sekar
- ORCID
- Saleheen, Danish
- Natarajan, Pradeep
- Armean, Irina M.
- Zhao, Wei
- Khetarpal, Sumeet A.
- Won, Hong-Hee
- Karczewski, Konrad J.
- Samocha, Kaitlin E.
- Gupta, Namrata
- Zaidi, Mozzam
- Trindade, Kevin
- Qamar, Nadeem
- Saghir, Tahir
- Ishaq, Mohammad
- Rasheed, Syed Zahed
- Mahmood, Khalid
- Do, Ron
- Krauss, Ronald M.
- MacArthur, Daniel G.
- Gabriel, Stacey
- Lander, Eric S.
- Daly, Mark J.
- Danesh, John
- Rader, Daniel J.
- Kathiresan, Sekar
- Venue
- Nature
- Published
- 2017-04
- Volume
- 544
- Issue
- 7649
- Pages
- 235-239
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5600291
- OpenAlex
- W2605659507
- Cited by
- 340
- References
- 64
- Citations by year
- 2026: 14 · 2025: 25 · 2024: 30 · 2023: 30 · 2022: 32 · 2021: 29 · 2020: 51 · 2019: 56 · 2018: 39 · 2017: 27
- FWCI
- 31.40
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nc-nd
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Apollo
- Funders
- Pfizer
- Donovan Family Foundation
- Wellcome Trust
- National Institute for Health and Care Research (NF-SI-0512-10165)
- British Heart Foundation (CH/12/2/29428, RG/13/13/30194, RG/16/4/32218, RG/08/014/24067)
- European Commission (279143, 279233)
- Fondation Leducq
- Cambridge University Hospitals (3819-1516-29, BRC 2012-2017, 3819-1617-25, 146281)
- National Institutes of Health
- Samsung
- Medical Research Council (MR/L003120/1, MR/M012816/1, MR/P013880/1)
- National Heart, Lung, and Blood Institute (R01HL107816)
- National Human Genome Research Institute (U54HG003067)
- National Institute of General Medical Sciences (R01GM104371)
- Fogarty International Center
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK043351)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- loss-of-function mutations, consanguinity, homozygous mutation, gene function, phenotypic association, exome sequencing, PLA2G7, cardiometabolic traits, Pakistani population, reverse genetics, serum lipoproteins, interleukin-8, apolipoprotein B
- MeSH terms
- Cytochrome P450 Family 2, Consanguinity, Coronary Disease, Dietary Fats, DNA Mutational Analysis, Fasting, Female, Gene Frequency, Genes, Homozygote, Humans, Male, Middle Aged, Myocardial Infarction, Pakistan, Pedigree, Phenotype, Phosphoproteins, Triglycerides, Cohort Studies, Interleukin-8, Gene Deletion, Sodium-Hydrogen Exchangers, Postprandial Period, Neuregulins, RNA Splice Sites, 1-Alkyl-2-acetylglycerophosphocholine Esterase, Apolipoprotein C-III, Genetic Association Studies, Reverse Genetics, Exome
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