Genetic and Environmental Risk for Chronic Pain and the Contribution of Risk Variants for Major Depressive Disorder: A Family-Based Mixed-Model Analysis
Genetic and Environmental Risk for Chronic Pain and the Contribution of Risk Variants for Major Depressive Disorder: A Family-Based Mixed-Model Analysis
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DOI：
10.1371/journal.pmed.1002090
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发表时间：
2016-08-01
期刊：
影响因子：
15.8
通讯作者：
Hocking, Lynne J.
中科院分区：
文献类型：
--
作者：
McIntosh, Andrew M.;Hall, Lynsey S.;Hocking, Lynne J.
慢性疼痛是一种非常普遍的疾病，也是导致残疾的重要原因，但其遗传和环境风险因素却知之甚少。它与重度抑郁症（MDD）的关系尤为重要。我们试图在苏格兰一代：苏格兰家庭健康研究（GS：SFHS）中测试遗传因素和共享和独特环境对慢性疼痛风险的贡献及其与MDD的相关性。然后，我们试图复制任何显着的发现在英国生物银行study.Methods和FindingsUsing基于家庭的混合模型分析，我们研究了遗传学和共享的家庭环境的贡献，慢性疼痛的配偶，兄弟姐妹和家庭关系。这些分析在GS：SFHS（n = 23，960）中进行，这是一项基于家庭和人群的研究，通过全科医生从苏格兰人群中招募个体。然后，我们检查和划分慢性疼痛和MDD之间的相关性，并估计遗传因素和共享环境在GS：SFHS中的贡献。最后，我们使用两项独立的全基因组关联研究的数据来测试慢性疼痛是否具有多基因结构，并检查精神疾病的基因组风险是否预测慢性疼痛以及慢性疼痛的基因组风险是否预测MDD。这些分析在GS：SFHS中进行，并在UK Biobank中重复进行，UK Biobank是一项来自英国人群的500，000人的研究，其中112，151人具有基因分型和表型数据。慢性疼痛是一种中度遗传性特征（遗传率= 38.4%，95% CI 33.6%至43.9%），在配偶中具有显著一致性（方差解释率为18.7%，95% CI 9.5%至25.1%）。慢性疼痛与抑郁症呈正相关（p = 0.13，95%CI 0.11至0.15，p = 2.72x10（-68）），并显示出因遗传原因在家族内聚集的趋势（遗传相关性= 0.51，95%CI 0.40至0.62，p = 8.24x10（-19））。使用独立的GWAS数据生成的疼痛多基因风险特征与两个GS中的慢性疼痛相关：SFHS（最大β = 6.18x10（-2），95%CI 2.84 x10（-2）至9.35 x10（-2），p = 4.3x10（-4））和UK Biobank（最大β = 5.68 x10（-2），95%CI 4.70x10（-2）至6.65x10（-2），p <3x 10（-4））。MDD的基因组风险也与GS中的慢性疼痛显著相关：SFHS（最大β = 6.62x10（-2），95%CI 2.82 x10（-2）至9.76 x10（-2），p = 4.3x10（-4））和UK Biobank（最大β = 2.56x10（-2），95%CI 1.62x10（-2）至3.63x10（-2），p <3x 10（-4））。目前的研究的局限性，包括配偶的影响可能是由于间接交配和相对较小的多基因风险评分effectsizes.ConclusionsGenetic因素，以及在合作伙伴或配偶的慢性疼痛的可能性，大大有助于个人的慢性疼痛的风险。慢性疼痛在遗传上与MDD相关，具有多基因结构，并且与MDD的多基因风险相关。
BackgroundChronic pain is highly prevalent and a significant source of disability, yet its genetic and environmental risk factors are poorly understood. Its relationship with major depressive disorder (MDD) is of particular importance. We sought to test the contribution of genetic factors and shared and unique environment to risk of chronic pain and its correlation with MDD in Generation Scotland:Scottish Family Health Study (GS:SFHS). We then sought to replicate any significant findings in the United Kingdom Biobank study.Methods and FindingsUsing family-based mixed-model analyses, we examined the contribution of genetics and shared family environment to chronic pain by spouse, sibling, and household relationships. These analyses were conducted in GS:SFHS (n = 23,960), a family-and population-based study of individuals recruited from the Scottish population through their general practitioners. We then examined and partitioned the correlation between chronic pain and MDD and estimated the contribution of genetic factors and shared environment in GS:SFHS. Finally, we used data from two independent genome-wide association studies to test whether chronic pain has a polygenic architecture and examine whether genomic risk of psychiatric disorder predicted chronic pain and whether genomic risk of chronic pain predicted MDD. These analyses were conducted in GS:SFHS and repeated in UK Biobank, a study of 500,000 from the UK population, of whom 112,151 had genotyping and phenotypic data. Chronic pain is a moderately heritable trait (heritability = 38.4%, 95% CI 33.6% to 43.9%) that is significantly concordant in spouses (variance explained 18.7%, 95% CI 9.5% to 25.1%). Chronic pain is positively correlated with depression (p = 0.13, 95% CI 0.11 to 0.15, p = 2.72x10(-68)) and shows a tendency to cluster within families for genetic reasons (genetic correlation = 0.51, 95% CI 0.40 to 0.62, p = 8.24x10(-19)). Polygenic risk profiles for pain, generated using independent GWAS data, were associated with chronic pain in both GS:SFHS (maximum beta = 6.18x10(-2), 95% CI 2.84 x10(-2) to 9.35 x10(-2), p = 4.3x10(-4)) and UK Biobank (maximum beta = 5.68 x 10(-2), 95% CI 4.70x10(-2) to 6.65x10(-2), p < 3x10(-4)). Genomic risk of MDD is also significantly associated with chronic pain in both GS:SFHS (maximum beta = 6.62x10(-2), 95% CI 2.82 x10(-2) to 9.76 x10(-2), p = 4.3x10(-4)) and UK Biobank (maximum beta = 2.56x10(-2), 95% CI 1.62x10(-2) to 3.63x10(-2), p < 3x10(-4)). Limitations of the current study include the possibility that spouse effects may be due to assortative mating and the relatively small polygenic risk score effect sizes.ConclusionsGenetic factors, as well as chronic pain in a partner or spouse, contribute substantially to the risk of chronic pain for an individual. Chronic pain is genetically correlated with MDD, has a polygenic architecture, and is associated with polygenic risk of MDD.