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

• DOI: 10.1007/s00439-011-1096-4
• Publication Date: 2011-09-28T05:35:00Z
• Authors: Jae-Jung Kim; Young-Mi Park; Kyu-Heum Baik; Hye-Yeon Choi; Gap-Seok Yang; InSong Koh; Jung-Ah Hwang; Jieun Lee; Yeon-Su Lee; Hwanseok Rhee; Tae Soo Kwon; Bok-Ghee Han; Karen E. Heath; Hiroshi Inoue; Han-Wook Yoo; Kiejung Park; Jong-Keuk Lee
• Keywords: Male; 0301 basic medicine; Korea; Genome, Human; Gene Expression Profiling; Sequence Analysis, DNA; Polymorphism, Single Nucleotide; Body Height; 03 medical and health sciences; Humans; Exome; Female; Growth Disorders

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.