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Genetic association studies: charting a path forward to GWAS

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Dr. Hirschhorn’s early work helped shape the conduct and interpretation of genetic association studies of polygenic traits and diseases, setting the stage for reproducible genome-wide association studies (GWAS).

 

Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JN. Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nature Genet. 2003; 33:177-82. (S)

 

Campbell CD, Ogburn EL, Lunetta KL, Lyon HN, Freedman ML, Groop LC, Altshuler D, Ardlie KG, Hirschhorn JN. Demonstrating stratification in a European-American population. Nature Genet. 2005; 37:868-72. (S)

 

McCarthy MI, Abecasis GR, Cardon LR, Goldstein DB, Little J, Ioannidis JPA, Hirschhorn JN. Genome wide association studies for complex traits: consensus, uncertainty and challenges. Nature Rev. Genet. 2008;9:356-69.

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Hirschhorn JN. Genomewide association studies – illuminating biologic pathways. New Engl. J. Med. 2009;360:1699-701. Full text here

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(S) = Student in the lab as first or co-first author

(P) = Postdoctoral fellow in the lab as first or co-first author

(A) = Analyst in the lab as first or co-first author

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GIANT (Genetic Investigation of ANthropometric Traits) consortium studies

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Dr. Hirschhorn chairs the GIANT consortium, which has discovered nearly all of the common variants known to influence human height and measures of obesity.

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Lango Allen H+, Estrada K+, Lettre G+, Berndt S+, Weedon MN+, Rivadeneira F+, … (many additional authors),  Abecasis GR*, Stefansson K*, Frayling TM*, Hirschhorn JN*. Hundreds of variants influence height and cluster in genomic loci and biological pathways. Nature 2010; 467:832-8. PMC2955183 (P)

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Locke AE+, Kahali B+, Berndt SI+, Justice AE+, Pers TH+, …  (many additional authors), North KE*, Ingelsson E*, Hirschhorn JN*, Loos RJF*, Speliotes EK*. Genetic studies of body mass index yield new insights for obesity biology. Nature 2015; 518:197–206. PMC4382211. (P)

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Marouli E+, Graff M+, Medina-Gomez C+, Lo KS+, Wood AR+, Kjaer TR+, Fine RS+, Lu Y+, …(many additional authors), Oxvig C*, Kutalik Z*, Rivadeneira F*, Loos RJ*, Frayling TM*, Hirschhorn JN*, Deloukas P*, Lettre G*. Rare and low-frequency coding variants alter human adult height. Nature 2017; 542:186-190. PMC5302847 (S)

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Yengo L+, Vedantam S+, Marouli E+, … (many additional authors), Okada Y*, Wood AR*, Visscher PM*, Hirschhorn JN*. A Saturated Map of Common Genetic Variants Associated with Human Height. Nature 2022;610:704-712. PMC9881884 (A)

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+,* contributed equally

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(S) = Student in the lab as first or co-first author

(P) = Postdoctoral fellow in the lab as first or co-first author

(A) = Analyst in the lab as first or co-first author

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New methods in genetics and metabolomics

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Dr. Hirschhorn’s lab works to develop new methods as needed, including for interpretation of GWAS results and utilizing unknown signals from untargeted metabolomics.

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Pers TH, Karjalainen JM, Chan Y, Westra, H-J, Wood AR, Yang J, Lui JC, Vedantam S, Gustafsson S, Esko T, Frayling T, Speliotes EK, GIANT consortium, Boehnke M, Raychaudhuri S, Fehrmann RSN, Hirschhorn JN*, Franke L*. Biological interpretation of genome-wide association studies using predicted gene function. Nature Comm. 2015; 6:5890. PMC4420238 (P)

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Fine RS, Pers TH, Amariuta T, Raychaudhuri S, Hirschhorn JN. Benchmarker: an unbiased, association-data-driven strategy to evaluate gene prioritization algorithms. Am J Hum Genet 2019;104:1025-1039. PMC6556976 (S)

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Hsu YH, Churchhouse C, Pers TH, Mercader JM, Metspalu A, Fischer K, Fortney K, Morgen EK, Gonzalez C, Gonzalez ME, Esko T, Hirschhorn JN. PAIRUP-MS: Pathway analysis and imputation to relate unknowns in profiles from mass spectrometry-based metabolite data. PLoS Comput Biol. 2019;15:e1006734. PMC6347288 (S)

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+,* contributed equally

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(S) = Student in the lab as first or co-first author

(P) = Postdoctoral fellow in the lab as first or co-first author

(A) = Analyst in the lab as first or co-first author

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Genetics of diet, metabolites, diabetic kidney disease, and hypermobile Ehlers Danlos syndrome

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Dr. Hirschhorn’s lab studies the genetics of diabetic kidney disease as part of the GENIE consortium, and hypermobile Ehlers Danlos syndrome as part of the HEDGE study. His lab also uses genetics to understand causal relationships between metabolism, diet, and obesity-related diseases.

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Mootha VK, Hirschhorn JN. Inborn variation in metabolism. Nature Genet. 2010;42:97-8.

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Esko T, Hirschhorn JN, Feldman HA, Hsu YH, Deik AA, Clish CB, Ebbeling CB, Ludwig DS. Metabolomic profiles as reliable biomarkers of dietary composition. Am J Clin Nutr. 2017;105:547-554. PMC5320413 (P)

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Salem RM+, Todd JN+, Sandholm N+, Cole JB+, Chen WM, Andrews D, Pezzolesi MG, McKeigue PM, Hiraki LT, Qiu C, Nair V, Di Liao C, Cao JJ, Valo E, Onengut-Gumuscu S, Smiles AM, McGurnaghan SJ, Haukka JK, Harjutsalo V, Brennan EP, van Zuydam N, Ahlqvist E, Doyle R, Ahluwalia TS, Lajer M, Hughes MF, Park J, Skupien J, Spiliopoulou A, Liu A, Menon R, Boustany-Kari CM, Kang HM, Nelson RG, Klein R, Klein BE, Lee KE, Gao X, Mauer M, Maestroni S, Caramori ML, de Boer IH, Miller RG, Guo J, Boright AP, Tregouet D, Gyorgy B, Snell-Bergeon JK, Maahs DM, Bull SB, Canty AJ, Palmer CNA, Stechemesser L, Paulweber B, Weitgasser R, Sokolovska J, Rovīte V, Pīrāgs V, Prakapiene E, Radzeviciene L, Verkauskiene R, Panduru NM, Groop LC, McCarthy MI, Gu HF, Möllsten A, Falhammar H, Brismar K, Martin F, Rossing P, Costacou T, Zerbini G, Marre M, Hadjadj S, McKnight AJ, Forsblom C, McKay G, Godson C, Maxwell AP, Kretzler M, Susztak K, Colhoun HM, Krolewski A, Paterson AD, Groop PH, Rich SS, Hirschhorn JN, Florez JC; SUMMIT Consortium, DCCT/EDIC Research Group, GENIE Consortium. Genome-Wide Association Study of Diabetic Kidney Disease Highlights Biology Involved in Glomerular Basement Membrane Collagen. J Am Soc Nephrol. 2019;30:2000-2016. PMC6779358 (P)

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Cole JB, Florez JC, Hirschhorn JN. Comprehensive genomic analysis of dietary habits in UK Biobank identifies hundreds of genetic associations. Nature Commun. 2020;11:1467. PMC7081342 (P)

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Hsu YH, Astley CM, Cole JB, Vedantam S, Mercader JM, Metspalu A, Fischer K, Fortney K, Morgen EK, Gonzalez C, Gonzalez ME, Esko T, Hirschhorn JN. Integrating untargeted metabolomics, genetically informed causal inference, and pathway enrichment to define the obesity metabolome. Int J Obes (Lond). 2020; 44:1596-1606. PMC7332400 (S)

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Goodman RP, Markhard AL, Shah H, Sharma R, Skinner OS, Clish CB, Deik A, Patgiri A, Hsu YH, Masia R, Noh HL, Suk S, Goldberger O, Hirschhorn JN, Yellen G, Kim JK, Mootha VK. Hepatic NADH reductive stress underlies common variation in metabolic traits. Nature 2020;583:122-126. PMC7536642

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+,* contributed equally

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(S) = Student in the lab as first or co-first author

(P) = Postdoctoral fellow in the lab as first or co-first author

(A) = Analyst in the lab as first or co-first author

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Genetics of monogenic disorders

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Dr. Hirschhorn’s lab has discovered genes responsible for monogenic disorders and is characterizing the contribution of rare variation in known disease genes to short stature and other disorders. His lab also helped define the role of variation in BCL11A in sickle cell disease, setting the stage for current gene editing therapies.

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Dauber A, Nguyen TT, Sochett E, Cole DE, Horst R, Abrams SA, Carpenter TO, Hirschhorn JN. Genetic defect in CYP24A1, the vitamin D 24-hydroxylase gene, in a patient with severe infantile hypercalcemia. J. Clin. Endocrinol. Metab. 2012; 97:E268-74. PMC3275367 (P)

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Abreu AP*, Dauber A*, Macedo DB, Noel SD, Brito VN, Gill JC, Cukier P, Thompson IR, Navarro VM, Gagliardi PC, Rodrigues T, Kochi C, Longui CA, Beckers D, de Zegher F, Montenegro LR, Mendonca BB, Carroll RS, Hirschhorn JN, Latronico AC+, Kaiser UB+. Central precocious puberty caused by mutations in the imprinted gene MKRN3. N Engl J Med. 2013; 368:2467-75. PMC3808195 (P)

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Wang SR, Carmichael H, Andrew SF, Miller TC, Moon JE, Derr MA, Hwa V, Hirschhorn JN, Dauber A. Large-scale pooled next-generation sequencing of 1077 genes to identify genetic causes of short stature. J Clin Endocrinol Metab. 2013; 98:E1428-37. PMC3733853 (S)

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Lettre G, Sankaran VG, Bezerra MA, Araújo AS, Uda M, Sanna S, Cao A, Schlessinger D, Costa FF, Hirschhorn JN, Orkin SH. DNA polymorphisms at the BCL11A, HBS1L-MYB, and beta-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease. Proc. Natl. Acad. Sci. U S A 2008;105:11869-74. PMC2491485 (P)

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+,* contributed equally

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(S) = Student in the lab as first or co-first author

(P) = Postdoctoral fellow in the lab as first or co-first author

(A) = Analyst in the lab as first or co-first author

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Evolutionary selection and human genetics

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Dr. Hirschhorn’s group has described signatures of evolutionary selection, especially related to height and lactase persistence, at individual genes and genome-wide.

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Bersaglieri T, Sabeti PC, Patterson N, Vanderploeg T, Schaffner SF, Drake JA, Rhodes M, Reich DE, Hirschhorn JN. Genetic signatures of strong recent positive selection at the lactase gene. Am. J. Hum. Genet. 2004; 74:1111-20. PMC1182075 (A)

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Turchin MC, Chiang CWK, Palmer CD, Sankararaman S, Reich D, GIANT Consortium, Hirschhorn JN. Evidence of widespread selection on standing variation in Europe at height-associated SNPs. Nature Genet. 2012; 44:1015-9. PMC3480734 (A) (S)

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Chan Y+, Holmen L+, Dauber A+, Vatten L, Havulinna AS, Skorpen F, Kvaløy K, Silander K, Nguyen TT, Willer C, Boehnke M, Perola M, Palotie A, Salomaa V, Hveem K, Frayling TM* Hirschhorn JN*, Weedon MN*. Common variants show predicted polygenic effects on height in the tails of the distribution, except in extremely short individuals. PLoS Genet. 2011; 7:e1002439. PMC3248463 (S) (P)

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+,* contributed equally

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(S) = Student in the lab as first or co-first author

(P) = Postdoctoral fellow in the lab as first or co-first author

(A) = Analyst in the lab as first or co-first author