Genome-wide Association Study of Idiopathic Osteonecrosis of the Femoral Head

Abstract

Idiopathic osteonecrosis of the femoral head (IONFH) is an ischemic disorder that causes bone necrosis of the femoral head, resulting in hip joint dysfunction. IONFH is a polygenic disease and steroid and alcohol have already known to increase its risk; however, the mechanism of IONFH remains to be elucidated. We performed a genome-wide association study using ~60,000 subjects and found two novel loci on chromosome 20q12 and 12q24. Big data analyses identified LINC01370 as a candidate susceptibility gene in the 20q12 locus. Stratified analysis by IONFH risk factors suggested that the 12q24 locus was associated with IONFH through drinking capacity. Our findings would shed new light on pathophysiology of IONFH.

Figure 1

Manhattan plot of imputed data (a) Idiopathic osteonecrosis of the femoral head vs BioBank Japan (BBJ), (b) alcohol-associated osteonecrosis of the femoral head (ONFH) vs BBJ, (c) alcohol-associated ONFH vs BBJ of heavy drinker (400 ml/day or more ethanol consumption), (d) steroid-associated ONFH vs BBJ, and (e) neither-associated ONFH vs BBJ. The SNPs with genome-wide significance were identified in (a) 12q24.11–12 and 20q12, (b) 12q24.11–13 and 20q12, (c) 20q12, and (d) 2q32 and 6p21. The red and blue lines represented the threshold of genome-wide significance (P = 5 × 10⁻⁸) and suggestive association threshold (P = 1 × 10⁻⁵), respectively.

Figure 2

Evaluation of the 20q12 locus (a) Regional association plot derived from the GWAS result of imputation analysis for idiopathic osteonecrosis of the femoral head. The region surrounded by distinct peaks of recombination rate (yellow box) was identified as a disease susceptibility locus. Only LINC01370 was within this locus. The color intensity reflected the extent of linkage disequilibrium index (r ²) with rs6028718 (in purple). Estimated recombination rates from the hg19/1000 Genomes Project Nov 2014 East Asian reference were shown as light-blue lines. (b) The topologically associated domain around the 20q12 locus (green box). Aside from LINC01370, this domain contained DHX35 (DEAH-box helicase 35) and MAFB (MAF bZIP transcription factor B).