Genome-Wide Association Study of Chronic Pain in Sickle Cell Disease

Background:

For many patients with sickle cell disease (SCD), episodes of acute pain occur within the context of debilitating persistent or chronic pain. Over half of adult patients report pain on more than half of the days, and almost a third experience pain on 95% of days. No previous GWAS studies have explored the association of genetic polymorphisms with chronic pain in SCD.

Methods:

We conducted a genome-wide association study (GWAS) involving 405 SCD patients using data from the screening phase of the Walk-PHaSST study (NCT00492531). Participants were age 12 years and older, with a median age of 35 years, and 53% were female; 73% had hemoglobin (Hb) SS, 18% had Hb SC, 4.0% had Hb Sβ + thalassemia, and 4.9% had other subtypes of SCD. Genotypic data were filtered to exclude SNPs with a call rate below 95%, deviations from Hardy-Weinberg equilibrium (P < 0.00001), or a minor allele frequency under 0.05, resulting in 9,874,538 SNPs for analysis. We performed a proportional odds logistic regression to evaluate the association between SNPs and self-reported chronic pain levels, rated on a 0 to 10 scale. Adjustments were made for age, sex, SCD subtype, alpha-thalassemia, hemoglobin concentration, hydroxyurea usage, and the first 10 principal components to control for population stratification.

Results:

Chronic pain was reported by 146 patients (36%). Three SNPs reached genome-wide significance: rs8026638 (p = 4.16 × 10^-8), rs7180285 (p = 4.64 × 10^-8), and rs10152723 (p = 4.96 × 10^-8). These SNPs, all in high linkage disequilibrium, are located on chromosome 15 within the intronic region of the CHD2 (Chromodomain Helicase DNA Binding Protein 2) gene.

Conclusions:

To the best of our knowledge, this is the first GWAS to identify a locus for chronic pain in SCD that exceeds genome-wide significance threshold. Analyzing a small but well-phenotyped cohort of individuals with SCD, we found association with three SNPs within the CHD2 gene. The CHD2 gene, part of a family of genes that modify chromatin structure to alter gene expression, has previously been associated with cognitive function, generalized myoclonic and atypical absence seizures, and abnormal pyramidal signs. Further validation in larger cohorts and additional biological studies are needed to confirm these associations and to further explore their potential modulating effects on pain pathophysiology and perception.

Gordeuk:Novartis: Research Funding; Incyte: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Emmaus: Consultancy, Research Funding; Modus Therapeutics: Consultancy.