LD block disorder-specific pleiotropic roles of novel CRHR1 in type 2 diabetes and depression disorder comorbidity.
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| Title: | LD block disorder-specific pleiotropic roles of novel CRHR1 in type 2 diabetes and depression disorder comorbidity. |
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| Authors: | del Bosque-Plata, Laura (AUTHOR), Amin, Mutaz (AUTHOR), González-Ramírez, Ricardo (AUTHOR), Wu, Rongling (AUTHOR), Postolache, Teodor T. (AUTHOR), Vergare, Michael (AUTHOR), Gordon, Derek (AUTHOR), Gragnoli, Claudia (AUTHOR) |
| Source: | European Archives of Psychiatry & Clinical Neuroscience. Jun2025, Vol. 275 Issue 4, p1025-1035. 11p. |
| Subjects: | Type 2 diabetes, Mental depression, Genotype-environment interaction, Hypothalamic-pituitary-adrenal axis, Corticotropin releasing hormone receptors, Linkage (Genetics), Single nucleotide polymorphisms, Comorbidity |
| Abstract: | Major depressive disorder (MDD) and type 2 diabetes (T2D) are complex disorders whose comorbidity can be due to hypercortisolism and may be explained by dysfunction of the corticotropin-releasing hormone receptor 1 (CRHR1) and cortisol feedback within the hypothalamic–pituitary–adrenal axis (HPA axis). To investigate the role of the CRHR1 gene in familial T2D, MDD, and MDD-T2D comorbidity, we tested 152 CRHR1 single-nucleotide-polymorphisms (SNPs), via 2-point parametric linkage and linkage disequilibrium (LD; i.e., association) analyses using 4 models, in 212 peninsular families with T2D and MDD. We detected linkage/LD/association to/with MDD and T2D with 122 (116 novel) SNPs. MDD and T2D had 4 and 3 disorder-specific novel risk LD blocks, respectively, whose risk variants reciprocally confirm one another. Comorbidity was conferred by 3 novel independent SNPs. In silico analyses reported novel functional changes, including the binding site of glucocorticoid receptor-alpha [GR-α] on CRHR1 for transcription regulation. This is the first report of CRHR1 pleiotropic linkage/LD/association with peninsular familial MDD and T2D. CRHR1 contribution to MDD is stronger than to T2D and may antecede T2D onset. Our findings suggest a new molecular-based clinical entity of MDD-T2D and should be replicated in other ethnic groups. [ABSTRACT FROM AUTHOR] |
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| Database: | Psychology and Behavioral Sciences Collection |
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| Abstract: | Major depressive disorder (MDD) and type 2 diabetes (T2D) are complex disorders whose comorbidity can be due to hypercortisolism and may be explained by dysfunction of the corticotropin-releasing hormone receptor 1 (CRHR1) and cortisol feedback within the hypothalamic–pituitary–adrenal axis (HPA axis). To investigate the role of the CRHR1 gene in familial T2D, MDD, and MDD-T2D comorbidity, we tested 152 CRHR1 single-nucleotide-polymorphisms (SNPs), via 2-point parametric linkage and linkage disequilibrium (LD; i.e., association) analyses using 4 models, in 212 peninsular families with T2D and MDD. We detected linkage/LD/association to/with MDD and T2D with 122 (116 novel) SNPs. MDD and T2D had 4 and 3 disorder-specific novel risk LD blocks, respectively, whose risk variants reciprocally confirm one another. Comorbidity was conferred by 3 novel independent SNPs. In silico analyses reported novel functional changes, including the binding site of glucocorticoid receptor-alpha [GR-α] on CRHR1 for transcription regulation. This is the first report of CRHR1 pleiotropic linkage/LD/association with peninsular familial MDD and T2D. CRHR1 contribution to MDD is stronger than to T2D and may antecede T2D onset. Our findings suggest a new molecular-based clinical entity of MDD-T2D and should be replicated in other ethnic groups. [ABSTRACT FROM AUTHOR] |
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| ISSN: | 09401334 |
| DOI: | 10.1007/s00406-023-01710-x |
