Abstract
Hip dysplasia, an abnormal laxity of the hip joint, is seen in humans as well as dogs and is one of the most common skeletal disorders in dogs. Canine hip dysplasia is considered multifactorial and polygenic, and a variety of chromosomal regions have been associated with the disorder. We performed a genome-wide association study in Dutch Labrador Retrievers, comparing data of nearly 18,000 single nucleotide polymorphisms (SNPs) in 48 cases and 30 controls using two different statistical methods. An individual SNP analysis based on comparison of allele frequencies with a χ2 statistic was used, as well as a simultaneous SNP analysis based on Bayesian variable selection. Significant association with canine hip dysplasia was observed on chromosome 8, as well as suggestive association on chromosomes 1, 5, 15, 20, 25 and 32. Next-generation DNA sequencing of the exons of genes of seven regions identified multiple associated alleles on chromosome 1, 5, 8, 20, 25 and 32 (p<0.001). Candidate genes located in the associated regions on chromosomes 1, 8 and 25 included LAMA2, LRR1 and COL6A3, respectively. The associated region on CFA20 contained candidate genes GDF15, COMP and CILP2. In conclusion, our study identified candidate genes that might affect susceptibility to canine hip dysplasia. These genes are involved in hypertrophic differentiation of chondrocytes and extracellular matrix integrity of basement membrane and cartilage. The functions of the genes are in agreement with the notion that disruptions in endochondral bone formation in combination with soft tissue defects are involved in the etiology of hip dysplasia.
Highlights
Hip dysplasia is characterised by an abnormal formation of the hip joint, causing incongruity and/or laxity of the joint, which can lead to osteoarthritis
Individual and Multiple single nucleotide polymorphisms (SNPs) Association Analysis Individual SNP association to canine hip dysplasia (CHD) was tested using a x2-based statistic for the comparison of allele frequencies using PLINK software, and revealed association to multiple chromosomal regions, including chromosome 1, 3, 5, 8, 11, 12, 13, 15, 19, 20, 25, 28, 32, 34 and the X chromosome (P-value,0.001, Figure 1)
A Bonferroni correction of a = 0.05 over 17,859 tests was performed to correct for multiple testing and only the region on chromosome 8 was significantly associated to CHD, with BICF2S23913508 located at position 33707642 bp of the reference genome CanFam2 as the most strongly associated SNP in this region
Summary
Hip dysplasia is characterised by an abnormal formation of the hip joint, causing incongruity and/or laxity of the joint, which can lead to osteoarthritis. It has been observed in several mammals, including humans, where it is referred to as developmental dysplasia of the hip (DDH), and in dogs where the term canine hip dysplasia (CHD) is used. In both species delayed femoral capital ossification, hip joint laxity and subluxation are observed in dysplastic hips [1] [2]. In Bulldogs up to 72% of the screened animals are affected (www.offa.org/stats_hip.html)
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