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. 2017 Jul;22(7):1015-1025.
doi: 10.1038/mp.2016.174. Epub 2016 Oct 25.

The PHF21B Gene Is Associated With Major Depression and Modulates the Stress Response

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Free PMC article

The PHF21B Gene Is Associated With Major Depression and Modulates the Stress Response

M-L Wong et al. Mol Psychiatry. .
Free PMC article

Abstract

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 'missing heritability' in MDD. Genome-wide association studies (GWAS) using single- and 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, <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.

Conflict of interest statement

The authors declare no competing interest and no income from pharmaceutical companies; an intellectual property application has been prepared to include the genetics findings of this work.

Figures

Figure 1
Figure 1
Flow diagram describing the process of filtering out low quality and functionally irrelevant variants. From 247 909 variants, 164 011 variants were discarded because they were monoallelic, had more than two alleles, had a call rate of <90%, or because their genotype proportions deviated from the expected ones as defined by the Hardy-–Weinberg (H–W) equilibrium law in both cases (patients with major depression) and controls at a P-value of 2 × 10−7. The remaining 83 898 variants were used for exome-wide association analysis. After additional functional filtering using several tools (SIFT, PolyPhen-2, MutationTaster, Gerp++ and phyloP) to exclude tolerated and conserved variants, and after the exclusion of non-exonic variants and variants in the control subjects with allelic frequency >0.01, the remaining 47 296 variants were used in rare variant analysis. MDD, major depressive disorder.
Figure 2
Figure 2
Manhattan plots for a GWAS of major depressive disorder (MDD) in a cohort of Mexican-American patients (n=203) and matched controls (n=196). Results of the GWAS using an additive model after correcting stratification by principal component analysis. In the inset, the first and second principal components that shows absence of genetic stratification (left box), and the Q–Q plot of observed vs expected of the −log10 (P-values, right box). The estimated Genomic Control ‘inflation factor’ λ was 1. GWAS, genome-wide association study.
Figure 3
Figure 3
Animal studies. (a) Paired t-test showed significantly increased floating time between the first (T1, baseline) and the second (T2, post-CRS) forced swim tests (FST) in the chronic restraint stress (CRS) non-resilient (nonresil, n=8) group but not in the CRS resilient (resil, n=11) and the non-CRS (n=6) groups. (b) One-way ANOVA showed that hippocampal Phf21b gene expression was significantly decreased in the CRS resil (resilient) group (n=11) but not in the CRS nonresil (non-resilient) group (n=8) comparing with the non-CRS group (n=6); columns=mean, bars=standard deviation of the mean. (s), seconds; AU, arbitrary units; **P<0.01; ***P<0.001.

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