Genome-wide Analysis of Body Proportion Classifies Height-Associated Variants by Mechanism of Action and Implicates Genes Important for Skeletal Development

Yingleong Chan; Rany M Salem; Yu-Han H Hsu; George McMahon; Tune H Pers; Sailaja Vedantam; Tonu Esko; Michael H Guo; Elaine T Lim; GIANT Consortium; Lude Franke; George Davey Smith; David P Strachan; Joel N Hirschhorn

doi:10.1016/j.ajhg.2015.02.018

Genome-wide Analysis of Body Proportion Classifies Height-Associated Variants by Mechanism of Action and Implicates Genes Important for Skeletal Development

Am J Hum Genet. 2015 May 7;96(5):695-708. doi: 10.1016/j.ajhg.2015.02.018. Epub 2015 Apr 9.

Authors

Affiliations

¹ Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA 02115, USA; Wyss Institute for Biologically Inspired Engineering, Harvard Medical School, Boston, MA 02115, USA. Electronic address: rigel@broadinstitute.org.
² Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA 02115, USA.
³ School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
⁴ Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA 02115, USA.
⁵ Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA 02115, USA; Estonian Genome Center, University of Tartu, Tartu 51010, Estonia.
⁶ Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen 9700 AB, the Netherlands.
⁷ School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK; MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2PR, UK.
⁸ Population Health Research Institute, St George's, University of London, London SW17 0RE, UK.
⁹ Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA 02115, USA. Electronic address: joelh@broadinstitute.org.

Abstract

Human height is a composite measurement, reflecting the sum of leg, spine, and head lengths. Many common variants influence total height, but the effects of these or other variants on the components of height (body proportion) remain largely unknown. We studied sitting height ratio (SHR), the ratio of sitting height to total height, to identify such effects in 3,545 African Americans and 21,590 individuals of European ancestry. We found that SHR is heritable: 26% and 39% of the total variance of SHR can be explained by common variants in European and African Americans, respectively, and global European admixture is negatively correlated with SHR in African Americans (r(2) ≈ 0.03). Six regions reached genome-wide significance (p < 5 × 10(-8)) for association with SHR and overlapped biological candidate genes, including TBX2 and IGFBP3. We found that 130 of 670 height-associated variants are nominally associated (p < 0.05) with SHR, more than expected by chance (p = 5 × 10(-40)). At these 130 loci, the height-increasing alleles are associated with either a decrease (71 loci) or increase (59 loci) in SHR, suggesting that different height loci disproportionally affect either leg length or spine/head length. Pathway analyses via DEPICT revealed that height loci affecting SHR, and especially those affecting leg length, show enrichment of different biological pathways (e.g., bone/cartilage/growth plate pathways) than do loci with no effect on SHR (e.g., embryonic development). These results highlight the value of using a pair of related but orthogonal phenotypes, in this case SHR with height, as a prism to dissect the biology underlying genetic associations in polygenic traits and diseases.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Black or African American / genetics
Body Height / genetics*
Chromosome Mapping
Female
Genome-Wide Association Study*
Humans
Leg Bones / growth & development
Male
Middle Aged
Multifactorial Inheritance / genetics*
Phenotype
Polymorphism, Single Nucleotide
White People / genetics

Abstract

Publication types

MeSH terms

Grants and funding