A PAX1 Enhancer Locus is Associated with Susceptibility to Idiopathic Scoliosis in Females

Overview

Journal Nat Commun

Specialty Biology

Date 2015 Mar 19

PMID 25784220

Citations 70

Authors

Swarkar Sharma

Douglas Londono

Walter L Eckalbar

Xiaochong Gao

Dongping Zhang

Kristen Mauldin

Ikuyo Kou

Atsushi Takahashi

Morio Matsumoto

Nobuhiro Kamiya

Karl K Murphy

Reuel Cornelia

John A Herring

Dennis Burns

Nadav Ahituv

Shiro Ikegawa

Derek Gordon

Carol A Wise

Affiliations

Soon will be listed here.

Abstract

Idiopathic scoliosis (IS) is a common paediatric musculoskeletal disease that displays a strong female bias. By performing a genome-wide association study (GWAS) of 3,102 individuals, we identify significant associations with 20p11.22 SNPs for females (P=6.89 × 10(-9)) but not males (P=0.71). This association with IS is also found in independent female cohorts from the United States of America and Japan (overall P=2.15 × 10(-10), OR=1.30 (rs6137473)). Unexpectedly, the 20p11.22 IS risk alleles were previously associated with protection from early-onset alopecia, another sexually dimorphic condition. The 174-kb associated locus is distal to PAX1, which encodes paired box 1, a transcription factor involved in spine development. We identify a sequence in the associated locus with enhancer activity in zebrafish somitic muscle and spinal cord, an activity that is abolished by IS-associated SNPs. We thus identify a sexually dimorphic IS susceptibility locus, and propose the first functionally defined candidate mutations in an enhancer that may regulate expression in specific spinal cells.

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