PDF(Pubmed)
Abstract：
UNASSIGNED: Epidemiologic studies have suggested co-morbidity between hypothyroidism and psychiatric disorders. However, the shared genetic etiology and causal relationship between them remain currently unclear.
UNASSIGNED: We assessed the genetic correlations between hypothyroidism and psychiatric disorders [anxiety disorders (ANX), schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP)] using summary association statistics from genome-wide association studies (GWAS). Two disease-associated pleiotropic risk loci and genes were identified, and pathway enrichment, tissue enrichment, and other analyses were performed to determine their specific functions. Furthermore, we explored the causal relationship between them through Mendelian randomization (MR) analysis.
UNASSIGNED: We found significant genetic correlations between hypothyroidism with ANX, SCZ, and MDD, both in the Linkage disequilibrium score regression (LDSC) approach and the high-definition likelihood (HDL) approach. Meanwhile, the strongest correlation was observed between hypothyroidism and MDD (LDSC: rg=0.264, P=7.35×10-12; HDL: rg=0.304, P=4.14×10-17). We also determined a significant genetic correlation between MDD with free thyroxine (FT4) and thyroid-stimulating hormone (TSH) levels. A total of 30 pleiotropic risk loci were identified between hypothyroidism and psychiatric disorders, of which the 15q14 locus was identified in both ANX and SCZ (P values are 6.59×10-11 and 2.10×10-12, respectively) and the 6p22.1 locus was identified in both MDD and SCZ (P values are 1.05×10-8 and 5.75×10-14, respectively). Sixteen pleiotropic risk loci were identified between MDD and indicators of thyroid function, of which, four loci associated with MDD (1p32.3, 6p22.1, 10q21.1, 11q13.4) were identified in both FT4 normal level and Hypothyroidism. Further, 79 pleiotropic genes were identified using Magma gene analysis (P<0.05/18776 = 2.66×10-6). Tissue-specific enrichment analysis revealed that these genes were highly enriched into six brain-related tissues. The pathway analysis mainly involved nucleosome assembly and lipoprotein particles. Finally, our two-sample MR analysis showed a significant causal effect of MDD on the increased risk of hypothyroidism, and BIP may reduce TSH normal levels.
UNASSIGNED: Our findings not only provided evidence of a shared genetic etiology between hypothyroidism and psychiatric disorders, but also provided insights into the causal relationships and biological mechanisms that underlie their relationship. These findings contribute to a better understanding of the pleiotropy between hypothyroidism and psychiatric disorders, while having important implications for intervention and treatment goals for these disorders.
UNASSIGNED: We assessed the genetic correlations between hypothyroidism and psychiatric disorders [anxiety disorders (ANX), schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP)] using summary association statistics from genome-wide association studies (GWAS). Two disease-associated pleiotropic risk loci and genes were identified, and pathway enrichment, tissue enrichment, and other analyses were performed to determine their specific functions. Furthermore, we explored the causal relationship between them through Mendelian randomization (MR) analysis.
UNASSIGNED: We found significant genetic correlations between hypothyroidism with ANX, SCZ, and MDD, both in the Linkage disequilibrium score regression (LDSC) approach and the high-definition likelihood (HDL) approach. Meanwhile, the strongest correlation was observed between hypothyroidism and MDD (LDSC: rg=0.264, P=7.35×10-12; HDL: rg=0.304, P=4.14×10-17). We also determined a significant genetic correlation between MDD with free thyroxine (FT4) and thyroid-stimulating hormone (TSH) levels. A total of 30 pleiotropic risk loci were identified between hypothyroidism and psychiatric disorders, of which the 15q14 locus was identified in both ANX and SCZ (P values are 6.59×10-11 and 2.10×10-12, respectively) and the 6p22.1 locus was identified in both MDD and SCZ (P values are 1.05×10-8 and 5.75×10-14, respectively). Sixteen pleiotropic risk loci were identified between MDD and indicators of thyroid function, of which, four loci associated with MDD (1p32.3, 6p22.1, 10q21.1, 11q13.4) were identified in both FT4 normal level and Hypothyroidism. Further, 79 pleiotropic genes were identified using Magma gene analysis (P<0.05/18776 = 2.66×10-6). Tissue-specific enrichment analysis revealed that these genes were highly enriched into six brain-related tissues. The pathway analysis mainly involved nucleosome assembly and lipoprotein particles. Finally, our two-sample MR analysis showed a significant causal effect of MDD on the increased risk of hypothyroidism, and BIP may reduce TSH normal levels.
UNASSIGNED: Our findings not only provided evidence of a shared genetic etiology between hypothyroidism and psychiatric disorders, but also provided insights into the causal relationships and biological mechanisms that underlie their relationship. These findings contribute to a better understanding of the pleiotropy between hypothyroidism and psychiatric disorders, while having important implications for intervention and treatment goals for these disorders.
摘要：
■流行病学研究表明甲状腺功能减退症和精神疾病之间的合并症。然而,它们之间共有的遗传病因和因果关系目前尚不清楚.
■我们评估了甲状腺功能减退和精神疾病[焦虑症（ANX），精神分裂症（SCZ），抑郁症（MDD），和双相情感障碍（BIP）]使用来自全基因组关联研究（GWAS）的汇总关联统计。确定了两个疾病相关的多效性风险位点和基因，和途径富集，组织富集，并进行其他分析以确定其特定功能。此外，我们通过孟德尔随机化(MR)分析探讨了两者之间的因果关系.
■我们发现甲状腺功能减退与ANX之间存在显著的遗传相关性，SCZ,MDD,在连锁不平衡评分回归（LDSC）方法和高清晰度似然（HDL）方法中。同时,甲状腺功能减退症与MDD之间的相关性最强（LDSC：rg=0.264，P=7.35×10-12；HDL：rg=0.304，P=4.14×10-17）。我们还确定了MDD与游离甲状腺素（FT4）和促甲状腺激素（TSH）水平之间的显着遗传相关性。在甲状腺功能减退症和精神疾病之间总共发现了30个多效性风险位点，其中在ANX和SCZ中均鉴定出15q14基因座（P值分别为6.59×10-11和2.10×10-12），在MDD和SCZ中均鉴定出6p22.1基因座（P值分别为1.05×10-8和5.75×10-14）。在MDD和甲状腺功能指标之间确定了16个多效性风险位点，其中，在FT4正常水平和甲状腺功能减退症中发现了4个与MDD相关的位点(1p32.3,6p22.1,10q21.1,11q13.4).Further,利用岩浆基因分析鉴定了79个多效性基因(P<0.05/18776=2.66×10-6)。组织特异性富集分析显示，这些基因高度富集到六个大脑相关组织中。通路分析主要涉及核小体组装和脂蛋白颗粒。最后,我们的双样本MR分析显示MDD对甲状腺功能减退症风险增加有显著的因果关系,和BIP可能降低TSH正常水平。
我们的发现不仅提供了甲状腺功能减退症和精神疾病共同遗传病因的证据，但也提供了对因果关系和生物机制的见解。这些发现有助于更好地理解甲状腺功能减退症和精神疾病之间的多效性。同时对这些疾病的干预和治疗目标具有重要意义。
■我们评估了甲状腺功能减退和精神疾病[焦虑症（ANX），精神分裂症（SCZ），抑郁症（MDD），和双相情感障碍（BIP）]使用来自全基因组关联研究（GWAS）的汇总关联统计。确定了两个疾病相关的多效性风险位点和基因，和途径富集，组织富集，并进行其他分析以确定其特定功能。此外，我们通过孟德尔随机化(MR)分析探讨了两者之间的因果关系.
■我们发现甲状腺功能减退与ANX之间存在显著的遗传相关性，SCZ,MDD,在连锁不平衡评分回归（LDSC）方法和高清晰度似然（HDL）方法中。同时,甲状腺功能减退症与MDD之间的相关性最强（LDSC：rg=0.264，P=7.35×10-12；HDL：rg=0.304，P=4.14×10-17）。我们还确定了MDD与游离甲状腺素（FT4）和促甲状腺激素（TSH）水平之间的显着遗传相关性。在甲状腺功能减退症和精神疾病之间总共发现了30个多效性风险位点，其中在ANX和SCZ中均鉴定出15q14基因座（P值分别为6.59×10-11和2.10×10-12），在MDD和SCZ中均鉴定出6p22.1基因座（P值分别为1.05×10-8和5.75×10-14）。在MDD和甲状腺功能指标之间确定了16个多效性风险位点，其中，在FT4正常水平和甲状腺功能减退症中发现了4个与MDD相关的位点(1p32.3,6p22.1,10q21.1,11q13.4).Further,利用岩浆基因分析鉴定了79个多效性基因(P<0.05/18776=2.66×10-6)。组织特异性富集分析显示，这些基因高度富集到六个大脑相关组织中。通路分析主要涉及核小体组装和脂蛋白颗粒。最后,我们的双样本MR分析显示MDD对甲状腺功能减退症风险增加有显著的因果关系,和BIP可能降低TSH正常水平。
我们的发现不仅提供了甲状腺功能减退症和精神疾病共同遗传病因的证据，但也提供了对因果关系和生物机制的见解。这些发现有助于更好地理解甲状腺功能减退症和精神疾病之间的多效性。同时对这些疾病的干预和治疗目标具有重要意义。
