Abstract
Background: Major depressive disorder (MDD) is a gene-environment disorder that affects approximately 350 million people worldwide. However, its under- lying genetic basis remains largely unknown. In this study, we investigated the role of functional genetic variants in MDD.
Methods: Whole-genome screening of functional variants were investigated in two cohorts: A discovery Los Angeles Mexican-American cohort (196 controls, 203 MDD) and a replication European-ancestry cohort (499 controls, 473 MDD). Controls had either high levels of stress (Mexican-American controls were primarily recent immi- grants) or high stress levels were given higher weights in our analysis (European-ancestry controls stress levels were accessed by questionnaires). Genome-wide association study (GWAS) and rare variant (regression- and permutation-based kernel-based adaptive cluster, KBAC) analyses were performed. Whole-genome sequencing and analyses were obtained in small subset of both cohorts. Pathway and network analyses were performed. Brain expression quantitative trait loci (eQTL) were extracted from the UK Brain Expression Consortium (UKBEC), and an animal model of chronic restraint stress was used to obtain behavioral, quantitative RT-PCR and Western blot data.
Results: In the Mexican-American cohort, we identified 44 common and rare functional variants associated to mild to moderate MDD. Pathway analysis disclosed that over- represented gene ontology processes included innate im- mune response, glutamate receptor signalling and detection of smell sensory perception. We replicated the PHF21B gene in the ethnically unrelated European-ancestry cohort. PHF21B variants contributed significantly to the levels of expression of this gene in the hippocampus and other brain areas. We will present new animal behavioral, molecular biology and biochemical data showing decreased hippocampal Phf21b gene and PHF21B protein express- ion in depressive-like behavior induced by chronic restraint stress.
Methods: Whole-genome screening of functional variants were investigated in two cohorts: A discovery Los Angeles Mexican-American cohort (196 controls, 203 MDD) and a replication European-ancestry cohort (499 controls, 473 MDD). Controls had either high levels of stress (Mexican-American controls were primarily recent immi- grants) or high stress levels were given higher weights in our analysis (European-ancestry controls stress levels were accessed by questionnaires). Genome-wide association study (GWAS) and rare variant (regression- and permutation-based kernel-based adaptive cluster, KBAC) analyses were performed. Whole-genome sequencing and analyses were obtained in small subset of both cohorts. Pathway and network analyses were performed. Brain expression quantitative trait loci (eQTL) were extracted from the UK Brain Expression Consortium (UKBEC), and an animal model of chronic restraint stress was used to obtain behavioral, quantitative RT-PCR and Western blot data.
Results: In the Mexican-American cohort, we identified 44 common and rare functional variants associated to mild to moderate MDD. Pathway analysis disclosed that over- represented gene ontology processes included innate im- mune response, glutamate receptor signalling and detection of smell sensory perception. We replicated the PHF21B gene in the ethnically unrelated European-ancestry cohort. PHF21B variants contributed significantly to the levels of expression of this gene in the hippocampus and other brain areas. We will present new animal behavioral, molecular biology and biochemical data showing decreased hippocampal Phf21b gene and PHF21B protein express- ion in depressive-like behavior induced by chronic restraint stress.
| Original language | English |
|---|---|
| Pages | S549 |
| Number of pages | 1 |
| Publication status | Published or Issued - 1 Nov 2017 |
| Event | American College of Neuropsychopharmacology (ACNP) 56th Annual Meeting - Palm Desert, United States Duration: 3 Dec 2017 → 7 Dec 2017 https://www.emedevents.com/c/medical-conferences-2017/american-college-of-neuropsychopharmacology-acnp-56th-annual-meeting |
Conference
| Conference | American College of Neuropsychopharmacology (ACNP) 56th Annual Meeting |
|---|---|
| Country/Territory | United States |
| City | Palm Desert |
| Period | 3/12/17 → 7/12/17 |
| Other | American College of Neuropsychopharmacology (ACNP) 56th Annual Meeting is organized by American College of Neuropsychopharmacology (ACNP) and would be held during JW Marriott Desert Springs Resort and Spa, Palm Desert, California, United States Of America. This cme conference has been approved with a maximum of 33.5 AMA PRA Category 1 Credits. |
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