located within a 3-kb haplotype block containing four other SNPs spanning intron 3 to intron 4 (ﬁgure 2). Six common haplotypes were identiﬁed in this block. Although the overall haplotype dis- tribution did not signiﬁcantly differ between cases and controls (p=0.09), the haplotype containing the minor T allele of rs941601 and the common A allele of rs8022616 was signiﬁcantly more fre- quent in cases (16%) than controls (10%), p=0.041. Conversely, the haplotype containing the common C allele of rs941601 and the variant G allele of rs8022616 was signiﬁcantly more common in controls (13%) than cases (7%), p=0.019 (table 4). The SERPINA6 SNP rs8022616 showed evidence of asso- ciation with a reduced likelihood of depression (proportional change=0.80, 95% CI 0.69 to 0.92, p=0.002 for each copy of the minor allele) and improved sleep quality (proportional change=0.86, 95% CI 0.76 to 0.98, p=0.02) for each copy of the minor allele in participants reporting sleep problems. Adjusting the association between rs8022616 and CWP for HAD depres- sion score and sleep quality score rendered it non-signiﬁcant (p=0.275) but the odds of having CWP was still reduced, pro- portional change=0.69, 95% CI 0.35 to 1.35. A single SNP in MC2R, rs11661134, was associated with an increased odds of having CWP in participants with one or two copies of the minor A allele compared to participants with zero copies (OR=2.24, 95% CI 1.14 to 4.39, p=0.02). There was no evidence of interaction between SNPs associated with CWP Figure 2 Linkage disequilibrium and haplotype block structure of SERPINA6 in the study population. Single nucleotide polymorphisms (SNPs) genotyped and their position in SERPINA6 are shown with pairwise linkage disequilibrium (LD; colour coded by r2 (white=0, black=1) and numbered by D′ (if no number D′=1)) and haplotype block structure as deﬁned by the conﬁdence bounds method.26 Table 4 Haplotype analysis of SERPINA6 with CWP Combination of SNPs rs941601–rs3790036– rs2144835–rs11629171– rs8022616–rs11622665 Overall distribution p value 0.09 Distribution of individual haplotypes Haplotype Case % Control % p Value CACCAG CATTGA CGTTAA CACCAA TATCAA CATCCA 0.21 0.07 0.16 0.14 0.16 0.26 0.22 0.13 0.17 0.15 0.10 0.23 0.881 0.019 0.651 0.762 0.041 0.401 CWP, chronic widespread pain. Ann Rheum Dis 2010;69:556–560. doi:10.1136/ard.2009.116137 Extended report with depression or sleep on CWP susceptibility and no evidence of association with SNPs in CRH, CRHR1, CRHBP, POMC or NR3C1 and CWP. DISCUSSION Here we report the ﬁndings of the ﬁrst population-based study to examine the role of HPA axis genes in musculoskeletal pain susceptibility. The ﬁndings suggest that genetic variation in the HPA axis, most notably in the corticosteroid binding globulin gene (SERPINA6), has a role in susceptibility to CWP and mus- culoskeletal pain in the population, however, comorbidities seem to explain some of the associations observed. Multiple SNPs in SERPINA6 were associated with the maxi- mum number of pain sites in participants reporting pain and two SNPs in this gene, rs941601 and rs8022616, also showed evidence of association with CWP and are located within a single haplo- type block. However, no effect of the haplotype over and above the individual effects of the SNPs was observed due to there being no evidence of recombination between the SNPs (D’=1). Genetic associations were also observed between a SNP in MC2R and CWP, and between SNPs in CRHBP and POMC with the maxi- mum number of pain sites in participants reporting pain. Genetic variation in the HPA axis may inﬂuence other pain- related factors such as psychological comorbidities and sleep quality. Consequently SNPs associating with pain were tested for association with these factors. The minor allele of the SERPINA6 SNP, rs8022616, was associated with a reduced likelihood of developing a depressive disorder and increased sleep quality. The minor C allele of the CRHBP SNP, rs1875999, was associated with increased likelihood of developing a depressive disorder and reduced sleep quality. This is in contrast to a previous report in which the common T allele of rs1875999 was signiﬁcantly asso- ciated with increased odds of having major depressive disorder in a Swedish population.28 These factors appear to explain the associations between these two SNPs and pain as they became non-signiﬁcant after adjustment for them; however, a reduced odds of having CWP was still observed in participants with the minor allele of rs8022616. Genetic variation in SERPINA6 could inﬂuence pain and psychological factors independently as previ- ous ﬁndings from the EPIFUND study showed that HPA axis dys- function increases the odds of developing CWP independently of depression and other psychological factors.29 Chronic fatigue syndrome (CFS) shares some similarity in its aetiology and symptoms with CWP and evidence of hypofunc- tion of the HPA axis in CFS has been reported.30 Therefore, the same genes may be associated with CFS and pain susceptibil- ity. Polymorphisms in NR3C1 have previously been associated with CFS31 and shown to distinguish between different classes of CFS.32 However, there was no evidence of association between SNPs in NR3C1 and musculoskeletal pain in this study. The most likely explanation for this is the modest sample size most notably in the previous studies but also in this study. Alternatively the pre- vious genetic associations observed with CFS may be speciﬁc to CFS rather than being genetic predictors for functional somatic syndromes. SNPs in NR3C1 have also been shown to inﬂuence cortisol levels.33 34 However, none of the SNPs that we observed in asso- ciation with pain here have as yet been tested for association with HPA axis function. This will be an important step in order to determine how the SNPs may be functioning via the HPA axis to inﬂuence pain susceptibility. One of the strengths of this study is the phenotypes used. Cases had reported CWP at at least two of the three time points, 559