The Hi-HOST Phenome Project (H2P2) seeks to interpret human genetic variation through the lens of cell biology. While genome-wide association studies (GWAS) have successfully identified hundreds of genetic variants associated with human diseases and traits, understanding the cell biological mechanisms underlying these associations remains a formidable challenge. H2P2 uses GWAS of cellular traits to provide a means to decipher how human genetic variation regulates cellular pathways, while also providing a system for experimental validation and mechanistic studies.

For GWAS of cellular traits, we developed and extensively validated a cellular GWAS platform called Hi-HOST (High-throughput human in vitro susceptibility testing) that uses pathogens to stimulate fundamental cellular pathways. Hi-HOST combines precise measurement of cellular phenotypes in lymphoblastoid cell lines (LCLs) with genome-wide association using 15 million genetic variants to identify genetic differences that underlie the phenotypic variation. Building on the Hi-HOST platform, H2P2 uses 8 different pathogens and 79 phenotypes encompassing cellular responses of infectivity and replication, cytokine levels, and host cell death. The purpose of the H2P2 Portal is to serve as a hypothesis generating engine through exploration of H2P2 summary statistics and individual SNP data.

Populations

• ESN - Esan in Nigeria
• GWD - Gambian in Western Divisions in the Gambia
• IBS - Iberian in Barcelona, Spain
• KHV - Kinh in Ho Chi Minh City, Vietnam
• Cells lines were provided by the Coriell Institute and are described in 1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. (2010) Nature 467, 1061-1073.

Pathogens

• Candida albicans
• Chlamydia trachomatis
• Mucor circinelloides
• Salmonella enterica serovar Typhi
• Salmonella enterica serovar Typhimurium
• Salmonella enterica serovar Typhimurium ΔsifA
• Staphylococcus aureus alpha toxin
• Toxoplasma gondii
• More in the future! Likely including Yersinia pestis, HIV, Zika virus, Influenza, Neisseria gonorrhoeae, Leishmania major. Contact us if you would like to collaborate on additional pathogens.

Publications utilizing the Hi-HOST approach

• Ko DC, Shukla KP, Fong C, Wasnick M, Brittnacher MJ, Wurfel MM, Holden TD, O’Keefe GE, Van Yserloo B, Akey JM, Miller SI. (2009) A genome-wide in vitro bacterial-infection screen reveals human variation in the host response associated with inflammatory disease. Am J Hum Genet. 85(2):214-27. PMC2725265.
• Ko DC, Gamazon ER, Shukla KP, Pfuetzner RA, Whittington D, Holden TD, Brittnacher MJ, Fong C, Radey M, Ogohara C, Stark AL, Akey JM, Dolan ME, Wurfel MM, Miller SI. (2012) Functional genetic screen of human diversity reveals that a methionine salvage enzyme regulates inflammatory cell death. PNAS. 109(35):2343-53. PMC3435171.
• Salinas RE, Ogohara C, Shukla KP, Thomas MI, Miller SI, and Ko DC. (2014) A cellular genome-wide association study reveals human variation in microtubule stability and a role in inflammatory cell death. Mol Biol Cell. 25(1):76-86. PMC3873895.
• Wang L, Ko ER, Gilchrist J, Pittman KJ, Rautanen A, Pirinen M, Thompson JW, Dubois LG, Langley RG, Jaslow SL, Salinas RE, Rouse DC, Moseley A, Mwarumba S, Njuguna P, Mturi N, Wellcome Trust Case-Control Consortium 2, The Kenyan Bacteraemia Study Group, Williams TN, Scott AG, Hill AVS, Woods CW, Ginsburg GS, Tsalik EL and Ko DC. (2017) Human genetic and metabolite variation reveal methylthioadenosine is a prognostic biomarker and inflammatory regulator in sepsis. Science Advances. 3(3). e1602096.
• Alvarez MI, Glover LC, Luo P, Wang L, Theusch E, Oehlers SH, Walton EM, Tram TT, Kuang YL, Rotter JI, McClean CM, Chinh NT, Medina MW, Tobin DM, Dunstan SJ, and Ko DC. (2017) Human genetic variation in VAC14 regulates Salmonella invasion and typhoid fever susceptibility through modulation of plasma membrane cholesterol. PNAS. 114(37):E7746-E7755. PMC5604016.

Publication on H2P2

• Wang L, Pittman KJ, Barker JR, Salinas RE, Stanaway IB, Williams GD, Carroll RJ, Balmat T, Ingham A, Gopalakrishnan AM, Gibbs KD, Antonia AL, Network Te, Heitman J, Lee SC, Jarvik GP, Denny JC, Horner SM, Delong MR, Valdivia RH, Crosslin DR, and Ko DC. (2018) An atlas of genetic variation for linking pathogen-induced cellular traits to human disease. Cell Host & Microbe. 24(2): 308-323.

Contacts

• Regarding H2P2: Dennis Ko
• Regarding H2P2 Portal: Liuyang Wang or Tom Balmat