The PHF21B gene is associated with major depression and modulates the stress response

Major depressive disorder (MDD) affects around 350 million people worldwide; however, the underlying genetic basis remains largely unknown. In this study, we took into account that MDD is a gene-environment disorder, in which stress is a critical component, and used whole-genome screening of functional variants to investigate the â missing heritability' in MDD. Genome-wide association studies (GWAS) using single- A nd multi-locus linear mixed-effect models were performed in a Los Angeles Mexican-American cohort (196 controls, 203 MDD) and in a replication European-ancestry cohort (499 controls, 473 MDD). Our analyses took into consideration the stress levels in the control populations. The Mexican-American controls, comprised primarily of recent immigrants, had high levels of stress due to acculturation issues and the European-ancestry controls with high stress levels were given higher weights in our analysis. We identified 44 common and rare functional variants associated with mild to moderate MDD in the Mexican-American cohort (genome-wide false discovery rate, FDR, less than 0.05), and their pathway analysis revealed that the three top overrepresented Gene Ontology (GO) processes were innate immune response, glutamate receptor signaling and detection of chemical stimulus in smell sensory perception. Rare variant analysis replicated the association of the PHF21B gene in the ethnically unrelated European-ancestry cohort. The TRPM2 gene, previously implicated in mood disorders, may also be considered replicated by our analyses. Whole-genome sequencing analyses of a subset of the cohorts revealed that European-ancestry individuals have a significantly reduced (50%) number of single nucleotide variants compared with Mexican-American individuals, and for this reason the role of rare variants may vary across populations. PHF21b variants contribute significantly to differences in the levels of expression of this gene in several brain areas, including the hippocampus. Furthermore, using an animal model of stress, we found that Phf21b hippocampal gene expression is significantly decreased in animals resilient to chronic restraint stress when compared with non-chronically stressed animals. Together, our results reveal that including stress level data enables the identification of novel rare functional variants associated with MDD. © 2017 Macmillan Publishers Limited.

• Fecha de publicación: 2017
• Institución: Universidad del Rosario
• Repositorio: Repositorio EdocUR - U. Rosario
• Idioma: eng
• OAI Identifier: oai:repository.urosario.edu.co:10336/22624
• Acceso en línea: https://doi.org/10.1038/mp.2016.174; https://repository.urosario.edu.co/handle/10336/22624
• Palabra clave: Glutamate receptor; Phd finger protein 21b; Transient receptor potential channel m2; Ubiquitin protein ligase; Unclassified drug; Adult; Aged; Animal experiment; Animal tissue; Article; Brain region; California; Chronic stress; Clinical trial (topic); Cohort analysis; Controlled study; Disease severity; European; Gene expression; Gene locus; Gene ontology; Genetic association; Genetic variability; Genome-wide association study; Genotype environment interaction; Haplotype; Heritability; Hippocampus; Human; Immigrant; Immobilization stress; Innate immunity; Major clinical study; Major depression; Male; Mexican american; Molecular pathology; Nonhuman; Phf21b gene; Priority journal; Rat; Sensory perception test; Single nucleotide polymorphism; Stress; Trpm2 gene; Whole genome sequencing; Case control study; Caucasian; Female; Genetic predisposition; Genetics; Major depression; Mental stress; Middle aged; Risk factor; Adult; Case-control studies; European continental ancestry group; Female; Gene expression; Genetic predisposition to disease; Genome-wide association study; Humans; Los angeles; Male; Mexican americans; Middle aged; Risk factors; major; single nucleotide; psychological; Depressive disorder; Polymorphism; Stress
• License: Abierto (Texto Completo)