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Exome sequencing and subsequent association studies identify five amino acid-altering variants influencing human height

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Abstract

Height is a highly heritable trait that involves multiple genetic loci. To identify causal variants that influence stature, we sequenced whole exomes of four children with idiopathic short stature. Ninety-five nonsynonymous single-nucleotide polymorphisms (nsSNPs) were selected as potential candidate variants. We performed association analysis in 740 cohort individuals and identified 11 nsSNPs in 10 loci (DIS3L2, ZBTB38, FAM154A, PTCH1, TSSC4, KIF18A, GPR133, ACAN, FAM59A, and NINL) associated with adult height (P < 0.05), including five novel loci. Of these, two nsSNPs (TSSC4 and KIF18A loci) were significant at P < 0.05 in the replication study (n = 1,000) and five (ZBTB38, FAM154A, TSSC4, KIF18A, and FAM59A loci) were significant at P < 0.01 in the combined analysis (n = 1,740). Together, the five nsSNPs accounted for approximately 2.5% of the height variation. This study demonstrated the utility of next-generation sequencing in identifying genetic variants and loci associated with complex traits.

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Abbreviations

CI:

Confidence interval

GWA:

Genome-wide association

HV:

Height velocity

ISS:

Idiopathic short stature

MA:

Monomelic amyotrophy

MAF:

Minor allele frequency

NS:

Noonan syndrome

OR:

Odds ratio

SD:

Standard deviations

SDS:

Standard deviation score

SE:

Standard error

SNP:

Single nucleotide polymorphism

SNV:

Single-nucleotide variant

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Acknowledgments

This work was supported by a grant from the Korea Science and Engineering Foundation (KOSEF) funded by the Korean government (MEST) (No. 2010-0016542), a grant from the Ministry of Health & Welfare of the Republic of Korea (A010384), and a grant from the Korea Centers for the Disease Control and Prevention (2009-N72001-00). Jae-Jung Kim was supported by National Research Foundation of Korea Grant funded by the Korean Government (Ministry of Education, Science and Technology; NRF-2011-355-C00109).

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Authors and Affiliations

  1. Asan Institute for Life Sciences, University of Ulsan College of Medicine, 388-1 Pungnap-2-Dong, Songpa-Gu, Seoul, 138-736, Korea

    Jae-Jung Kim, Young-Mi Park & Jong-Keuk Lee

  2. Macrogen Inc, Seoul, Korea

    Kyu-Heum Baik, Hye-Yeon Choi & Gap-Seok Yang

  3. Department of Physiology, College of Medicine, Hanyang University, Seoul, Korea

    InSong Koh

  4. National Cancer Center, Goyang, Korea

    Jung-Ah Hwang, Jieun Lee & Yeon-Su Lee

  5. Center for Genome Science, National Institute of Health, Chungwon, Korea

    Hwanseok Rhee, Tae Soo Kwon, Bok-Ghee Han & Kiejung Park

  6. Institute of Medical and Molecular Genetics, Hospital Universitario La Paz, Madrid, Spain

    Karen E. Heath

  7. Division of Genetic Information, Institute for Genome Research, The University of Tokushima, Tokushima, Japan

    Hiroshi Inoue

  8. Department of Pediatrics, University of Ulsan College of Medicine, Seoul, Korea

    Han-Wook Yoo

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  1. Jae-Jung Kim
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Corresponding author

Correspondence to Jong-Keuk Lee.

Additional information

H.-W. Yoo, K. Park and J.-K. Lee contributed equally to this work.

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Kim, JJ., Park, YM., Baik, KH. et al. Exome sequencing and subsequent association studies identify five amino acid-altering variants influencing human height. Hum Genet 131, 471–478 (2012). https://doi.org/10.1007/s00439-011-1096-4

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