Barbara Dowling

Finer linkage mapping of a primary hip osteoarthritis susceptibility locus on chromosome 6

Primary osteoarthritis (OA) is a common late-onset disease that exhibits complex genetic transmittance. A previous genome-wide linkage scan of OA affected sibling pair families (ascertained by total joint replacement surgery) identified a region of suggestive linkage on chromosome 6, with a maximum multipoint-LOD score (MLS) of 2.9 in 194 families containing sibling pairs concordant for total hip replacement (THR-families). However, up to 50 cM of the chromosome had a multipoint-LOD score >2.0, vvindicating that the susceptibility locus was poorly mapped. We have now genotyped chromosome 6 to a higher density in an expanded cohort of 378 THR-families. We obtained an MLS of 2.8 to an 11.4 cM interval defined by markers D6S452 and 509-8B2, which map between 70.5 to 81.9 cM from the 6p-telomere. Stratification by gender revealed that this linkage was completely accounted for by female THR-families (n=146), with an MLS of 4.0 and with the highest two-point LOD score being 4.6 for marker D6S1573 (75.9 cM). The 11.4 cM interval just encompasses the candidate gene COL9A1 (81.9 cM). We identified and then genotyped twenty common single nucleotide polymorphisms (SNPs) from within COL9A1 in the 146 probands from our female THR-families and in 215 age-matched female controls. No SNP allele, genotype or haplotype demonstrated association to disease. Overall, we have narrowed the chromosome 6 OA susceptibility locus to a point at which linkage disequilibrium/association analysis is feasible, we have demonstrated that this locus is female specific, and found no evidence that COL9A1 encodes for the susceptibility.

Genetics of osteoarthritis

Epidemiological studies have demonstrated a major genetic component to osteoarthritis (OA), with heritability estimates of over 50% for most joint sites. These studies have also highlighted differences in the degree of OA heritability between joint sites and between the sexes, implying a high level of heterogeneity. We published a genome-wide scan in 1999. We had focused on families containing siblings with severe large-joint OA ascertained by joint-replacement surgery. Our data showed that OA genetic susceptibility did exhibit joint specificity and that this susceptibility had a greater role in female disease. During the past 5 years we have been investigating our linkage regions and we have so far identified FRZB (chromosome 2q32.1), COL9A1 (6q12-q13), BMP5 (6p12.1) and IL4R (16p12.1-p11.2) as encoding for OA susceptibility. Common variants at these genes affect either the structural properties of the protein (FRZB and IL4R) or the transcription of the gene (BMP5 and COL9A1). The variants are particularly relevant to the development of hip OA in females. What is particularly interesting about our recent discoveries is that the proteins encoded for by IL4R, BMP5 and FRZB are involved in chondrocyte cell signalling and signal transduction pathways. It appears probable, therefore, that OA genetic risk for the hip is principally accounted for by aberrant cell signalling. This was not anticipated. In this presentation I will focus on our latest genetic findings. I will also discuss the results from other studies. A number of OA genome-wide scans have been performed, some on large joints and others investigating hand disease. Many loci appear unique to one particular study, with only some loci being positive in multiple studies. The reasons for this will be discussed. A concern often expressed at orthopaedic and rheumatology meetings is that genetic linkages and associations are not consistently reproduced. These are reasonable criticisms but it needs to be remembered that the genetic component of a complex trait such as OA will not be mediated by fully penetrant risk alleles. Instead, any one allele will contribute only a fraction of the overall risk and this allele will, by chance, have varying frequencies in different cohorts. It is unreasonable, therefore, to expect a linkage or an association in one cohort to be replicated in all cohorts.