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A genome-wide polygenic approach to HIV acquisition uncovers link to inflammatory bowel disease and identifies potential novel genetic variants

Robert A. Power, Christian W. Thorball, Istvan Bartha, John R.B. Perry, Paul J McLaren, Tulio de Oliveira, Jacques Fellay
doi: https://doi.org/10.1101/145383
Robert A. Power
1Africa Health Research Institute, University College London, Durban, South Africa
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Christian W. Thorball
2School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
3Swiss Institute of Bioinformatics, Lausanne, Switzerland
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Istvan Bartha
2School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
3Swiss Institute of Bioinformatics, Lausanne, Switzerland
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John R.B. Perry
4MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Box 285 Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.
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Paul J McLaren
5JC Wilt Infectious Diseases Research Centre, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Canada
6Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Canada
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Tulio de Oliveira
7Nelson R. Mandela School of Medicine, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
8Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
9Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa
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Jacques Fellay
2School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
3Swiss Institute of Bioinformatics, Lausanne, Switzerland
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Abstract

Polygenic approaches using genome-wide data have been hugely successful in confirming and quantifying the heritability of complex human traits. Here, we highlight their ability to identify potential novel risk variants by looking for variants with pleiotropic effect in genetically overlapping phenotypes.

We used LD Score Regression in a sample of 6,315 HIV+ European individuals and 7,247 controls to test for phenotypes genetically overlapping with susceptibility to HIV-1 infection. Using LD Hub, a web tool that performs LD Score Regression, identified two phenotypes with significant genetic overlap: schizophrenia (rG =0.19, p=0.0007 and ulcerative colitis (rG=0.22, p= 0.0061). We further showed that the genetic overlap between HIV acquisition and schizophrenia is likely driven in part by their shared overlap with cannabis use and sexual behavior. BUMHBOX analyses suggested that these genetic overlaps were driven by genome-wide pleiotropy with HIV acquisition rather than heterogeneity within the HIV acquisition sample. The two diseases identified as genetically overlapping with HIV-1 acquisition have >100 associated variants, and we tested if any of them significantly associated with HIV acquisition. We observed three variants that exceeded our threshold for statistical significance. Two of these were eQTLs in whole blood for genes coding for proteins suspected to be involved in HIV biology: rs1819333 in CCR6 (p=0.0002) and rs4932178 in FURIN (p=0.00033). However, no signal was found for these variants in two smaller African samples totaling 1015 cases and 963 controls, though the mode of acquisition and genetic architecture of these populations differed.

These results highlight the ability to use polygenic methods to gain new insights into complex diseases and identify potential associations with individual variants. Crucially, the leveraging of existing, publically available data makes these methods a cost-effective approach. In this case, our results add to the evidence for the role of risk taking behavior and inflammation of the bowel in HIV acquisition.

Author Summary The biology of what puts certain individuals at greater risk of HIV acquisition is poorly understood. Using several novel polygenic methods, we identify supporting evidence for two important factors leading to acquisition. First, the role of an individual’s genetic predisposition to risk taking behaviours such as number of sexual partners, age at first sexual intercourse drug use, and mental health problems. Second, the role of gut inflammation, in particular a genetic overlap between HIV acquisition with inflammatory bowel disease and the potential role of CCR6 during infection.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted June 12, 2017.
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A genome-wide polygenic approach to HIV acquisition uncovers link to inflammatory bowel disease and identifies potential novel genetic variants
Robert A. Power, Christian W. Thorball, Istvan Bartha, John R.B. Perry, Paul J McLaren, Tulio de Oliveira, Jacques Fellay
bioRxiv 145383; doi: https://doi.org/10.1101/145383
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A genome-wide polygenic approach to HIV acquisition uncovers link to inflammatory bowel disease and identifies potential novel genetic variants
Robert A. Power, Christian W. Thorball, Istvan Bartha, John R.B. Perry, Paul J McLaren, Tulio de Oliveira, Jacques Fellay
bioRxiv 145383; doi: https://doi.org/10.1101/145383

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