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Polygenic heritability estimates in pharmacogenetics: focus on asthma and related phenotypes

McGeachie, Michael J.a,b,e; Stahl, Eli A.f; Himes, Blanca E.a,b,e; Pendergrass, Sarah A.g; Lima, John J.h; Irvin, Charles G.i; Peters, Stephen P.j; Ritchie, Marylyn D.g; Plenge, Robert M.e,c; Tantisira, Kelan G.b,d,e

Pharmacogenetics and Genomics: June 2013 - Volume 23 - Issue 6 - p 324–328
doi: 10.1097/FPC.0b013e3283607acf
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Although accurate measures of heritability are required to understand the pharmacogenetic basis of drug treatment response, these are generally not available, as it is unfeasible to give medications to individuals for which treatment is not indicated. Using a polygenic linear mixed modeling approach, we estimated lower bounds on the heritability of asthma and the heritability of two related drug–response phenotypes, bronchodilator response and airway hyperreactivity, using genome-wide single nucleotide polymorphism (SNP) data from existing asthma cohorts. Our estimate of the heritability for bronchodilator response is 28.5% (SE 16%, P=0.043) and airway hyperresponsiveness is 51.1% (SE 34%, P=0.064), whereas we estimate asthma genetic liability at 61.5% (SE 16%, P<0.001). Our results agree with the previously published estimates of the heritability of these traits, suggesting that the linear mixed modeling method is useful for computing the heritability of other pharmacogenetic traits. Furthermore, our results indicate that multiple SNP main effects, including SNPs as yet unidentified by genome-wide association study methods, together explain a sizable portion of the heritability of these traits.

aPartners Healthcare Center for Personalized Genetic Medicine

bDepartment of Medicine, Channing Division of Network Medicine

cDepartment of Medicine, Division of Rheumatology, Immunology and Allergy

dDepartment of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital

eHarvard Medical School, Boston, Massachusetts

fMt Sinai School of Medicine, Division of Psychiatric Genomics, New York, New York

gDepartment of Biochemistry and Molecular Biology, Center for Systems Genomics, Pennsylvania State University, University Park, Pennsylvania

hCenters for Clinical Pediatric Pharmacology and Pharmacogenetics, Nemours Children’s Clinic, Jacksonville, Florida

iDepartment of Medicine and Physiology, Vermont Lung Center, University of Vermont, Burlington, Vermont

jCenter for Genomics and Personalized Medicine Research, Wake Forest University, Winston-Salem, North Carolina, USA

Correspondence to Michael J. McGeachie, PhD, Department of Medicine, Channing Division of Network Medicine, Brigham and Women’s Hospital, 181 Longwood Ave, Boston, MA 02115, USA Tel: +617 525 2270; fax: +617 525 0958; e-mail: mmcgeach@csail.mit.edu

Received October 9, 2012

Accepted February 11, 2013

© 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins