Functional Genomics Analysis to Disentangle the Role of Genetic Variants in Major Depression.
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ABSTRACT:
SUBMITTER: Perez-Granado J
PROVIDER: S-EPMC9320424 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Osteoarthritis (OA) and major depression (MD) are two debilitating disorders that frequently co-occur and affect millions of the elderly each year. Despite the greater symptom severity, poorer clinical outcomes, and increased mortality of the comorbid conditions, we have a limited understanding of their etiologic relationships. In this study, we conducted the first cross-disorder investigations of OA and MD, using genome-wide association data representing over 247K cases and 475K controls. Along with significant positive genome-wide genetic correlations (r g = 0.299 ± 0.026, p = 9.10 × 10-31), Mendelian randomization (MR) analysis identified a bidirectional causal effect between OA and MD (βOA → MD = 0.09, SE = 0.02, z-score p-value < 1.02 × 10-5; βMD → OA = 0.19, SE = 0.026, p < 2.67 × 10-13), indicating genetic variants affecting OA risk are, in part, shared with those influencing MD risk. Cross-disorder meta-analysis of OA and MD identified 56 genomic risk loci (P meta ≤ 5 × 10-8), which show heightened expression of the associated genes in the brain and pituitary. Gene-set enrichment analysis highlighted "mechanosensory behavior" genes (GO:0007638; P gene_set = 2.45 × 10-8) as potential biological mechanisms that simultaneously increase susceptibility to these mental and physical health conditions. Taken together, these findings show that OA and MD share common genetic risk mechanisms, one of which centers on the neural response to the sensation of mechanical stimulus. Further investigation is warranted to elaborate the etiologic mechanisms of the pleiotropic risk genes, as well as to develop early intervention and integrative clinical care of these serious conditions that disproportionally affect the aging population.
| S-EPMC8481820 | biostudies-literature
Project description:ImportanceAlcohol dependence (AD) and major depression (MD) are leading causes of disability that often co-occur. Genetic epidemiologic data have shown that AD and MD share a common possible genetic cause. The molecular nature of this shared genetic basis is poorly understood.ObjectivesTo detect genetic risk variants for comorbid AD and MD and to determine whether polygenic risk alleles are shared with neuropsychiatric traits or subcortical brain volumes.Design, setting, and participantsThis genome-wide association study analyzed criterion counts of comorbid AD and MD in African American and European American data sets collected as part of the Yale-Penn study of the genetics of drug and alcohol dependence from February 14, 1999, to January 13, 2015. After excluding participants never exposed to alcohol or with missing information for any diagnostic criterion, genome-wide association studies were performed on 2 samples (the Yale-Penn 1 and Yale-Penn 2 samples) totaling 4653 African American participants and 3169 European American participants (analyzed separately). Tests were performed to determine whether polygenic risk scores derived from potentially related traits in European American participants could be used to estimate comorbid AD and MD.Main outcomes and measuresComorbid criterion counts (ranging from 0 to 14) for AD (7 criteria) and MD (9 criteria, scaled to 7) as defined by the DSM-IV.ResultsOf the 7822 participants (3342 women and 4480 men; mean [SD] age, 40.1 [10.7] years), the median comorbid criterion count was 6.2 (interquartile range, 2.3-10.9). Under the linear regression model, rs139438618 at the semaphorin 3A (SEMA3A [OMIM 603961]) locus was significantly associated with AD and MD comorbidity in African American participants in the Yale-Penn 1 sample (β = 0.89; 95% CI, 0.57-1.20; P = 2.76 × 10-8). In the independent Yale-Penn 2 sample, the association was also significant (β = 0.83; 95% CI, 0.39-1.28; P = 2.06 × 10-4). Meta-analysis of the 2 samples yielded a more robust association (β = 0.87; 95% CI, 0.61-1.12; P = 2.41 × 10-11). There was no significant association identified in European American participants. Analyses of polygenic risk scores showed that individuals with a higher risk of neuroticism (β = 1.01; 95% CI, 0.50-1.52) or depressive symptoms (β = 0.87; 95% CI, 0.32-1.42) and a lower level of subjective well-being (β = -0.94; 95% CI, -1.46 to -0.42) and educational attainment (β = -1.00, 95% CI, -1.57 to -0.44) had a higher level of AD and MD comorbidity, while larger intracranial (β = 1.07; 95% CI, 0.50 to 1.64) and smaller putamen volumes (β = -1.16; 95% CI, -1.86 to -0.46) were associated with higher risks of AD and MD comorbidity.Conclusions and relevanceSEMA3A variation is significantly and replicably associated with comorbid AD and MD in African American participants. Analyses of polygenic risk scores identified pleiotropy with neuropsychiatric traits and brain volumes. Further studies are warranted to understand the biological and genetic mechanisms of this comorbidity, which could facilitate development of medications and other treatments for comorbid AD and MD.
| S-EPMC6331050 | biostudies-literature
Project description:Major depressive disorder (MDD) is a complex psychiatric condition with strong genetic predisposition. The association of MDD with genetic polymorphisms, such as Val66Met (rs6265), in the brain derived neurotrophic factor (BDNF), have been reported in many studies and the results were conflicting. In this study, we performed a systematic literature search and conducted random-effects meta-analysis to evaluate genetic variants in BDNF with MDD. A gene-based analysis was also conducted to investigate the cumulative effects of genetic polymorphisms in BDNF. A total of 28 studies from 26 published articles were included in our analysis. Meta-analysis yielded an estimated odds ratio (OR) of 0.96 (95% CI: 0.89-1.05; P = 0.402) for Val66Met (rs6265), 0.83 (95% CI: 0.67-1.04; P = 0.103) for 11757C/G, 1.16 (95% CI: 0.74-1.82; P = 0.527) for 270T/C, 1.03 (95% CI: 0.18-5.75; P = 0.974) for 712A/G and 0.98 (95% CI: 0.85-1.14; P = 0.831) for rs988748. The gene-based analysis indicated that BDNF is not associated with MDD (P > 0.21). Our updated meta- and novel gene-based analyses provide no evidence of the association of BDNF with major depression.
| S-EPMC3725128 | biostudies-literature
Project description:SLC6A15 is a neuron-specific neutral amino acid transporter that belongs to the solute carrier 6 gene family. This gene family is responsible for presynaptic re-uptake of the majority of neurotransmitters. Convergent data from human studies, animal models and pharmacological investigations suggest a possible role of SLC6A15 in major depressive disorder. In this work, we explored potential functional variants in this gene that could influence the activity of the amino acid transporter and thus downstream neuronal function and possibly the risk for stress-related psychiatric disorders. DNA from 400 depressed patients and 400 controls was screened for genetic variants using a pooled targeted re-sequencing approach. Results were verified by individual re-genotyping and validated non-synonymous coding variants were tested in an independent sample (N = 1934). Nine variants altering the amino acid sequence were then assessed for their functional effects by measuring SLC6A15 transporter activity in a cellular uptake assay. In total, we identified 405 genetic variants, including twelve non-synonymous variants. While none of the non-synonymous coding variants showed significant differences in case-control associations, two rare non-synonymous variants were associated with a significantly increased maximal (3)H proline uptake as compared to the wildtype sequence. Our data suggest that genetic variants in the SLC6A15 locus change the activity of the amino acid transporter and might thus influence its neuronal function and the risk for stress-related psychiatric disorders. As statistically significant association for rare variants might only be achieved in extremely large samples (N >70,000) functional exploration may shed light on putatively disease-relevant variants.
| S-EPMC3712998 | biostudies-literature
Project description:Major depressive disorder (MDD) is the most common psychiatric disorder and the second overall cause of disability. Even though a significant amount of the variance in the MDD phenotype is explained by inheritance, specific genetic variants conferring susceptibility to MDD explain only a minimal proportion of MDD causality. Moreover, genome-wide association studies have only identified two small-sized effect loci that reach genome-wide significance. In this study, a group of Mexican-American patients with MDD and controls recruited for a pharmacogenetic study were genotyped for nonsynonymous single-nucleotide polymorphisms (nsSNPs) and used to explore the interactions of multiple functional genetic variants with risk-classification tree analysis. The risk-classification tree analysis model and linkage disequilibrium blocks were used to replicate exploratory findings in the database of genotypes and phenotypes (dbGaP) for major depression, and pathway analysis was performed to explore potential biological mechanisms using the branching events. In exploratory analyses, we found that risk-classification tree analysis, using 15 nsSNPs that had a nominal association with MDD diagnosis, identified multiple increased-MDD genotype clusters and significant additive interactions in combinations of genotype variants that were significantly associated with MDD. The results in the dbGaP for major depression disclosed a multidimensional dependent phenotype constituted of MDD plus significant modifiers (smoking, marriage status, age, alcohol abuse/dependence and gender), which then was used for the association tree analysis. The reconstructed tree analysis for the dbGaP data showed robust reliability and replicated most of the genes involved in the branching process found in our exploratory analyses. Pathway analysis using all six major events of branching (PSMD9, HSD3B1, BDNF, GHRHR, PDE6C and PDLIM5) was significant for positive regulation of cellular and biological processes that are relevant to growth and organ development. Our findings not only provide important insights into the biological pathways underlying innate susceptibility to MDD but also offer a predictive framework based on interactions of multiple functional genetic variants and environmental factors. These findings identify novel targets for therapeutics and for translation into preventive, clinical and personalized health care.
| S-EPMC3359641 | biostudies-literature
Project description:CONTEXT:Despite recent progress in describing the common neural circuitry of emotion and stress processing, the bases of individual variation are less well understood. Genetic variants that underlie psychiatric disease have proven particularly difficult to elucidate. Functional genetic variation of neuropeptide Y (NPY) was recently identified as a source of individual differences in emotion. Low NPY levels have been reported in major depressive disorder (MDD). OBJECTIVE:To determine whether low-expression NPY genotypes are associated with negative emotional processing at 3 levels of analysis. DESIGN:Cross-sectional, case-control study. SETTING:Academic medical center. PARTICIPANTS:Among 44 individuals with MDD and 137 healthy controls, 152 (84%) had an NPY genotype classified as low, intermediate, or high expression according to previously established haplotype-based expression data. MAIN OUTCOME MEASURES:Healthy subjects participated in functional magnetic resonance imaging while viewing negative (vs neutral) words (n = 58) and rated positive and negative affect during a pain-stress challenge (n = 78). Genotype distribution was compared between 113 control subjects and 39 subjects with MDD. RESULTS:Among healthy individuals, negatively valenced words activated the medial prefrontal cortex. Activation within this region was inversely related to genotype-predicted NPY expression (P = .03). Whole-brain regression of responses to negative words showed that the rostral anterior cingulate cortex activated in the low-expression group and deactivated in the high-expression group (P < .05). During the stress challenge, individuals with low-expression NPY genotypes reported more negative affective experience before and after pain (P = .002). Low-expression NPY genotypes were overrepresented in subjects with MDD after controlling for age and sex (P = .004). Population stratification did not account for the results. CONCLUSIONS:These findings support a model in which NPY genetic variation predisposes certain individuals to low NPY expression, thereby increasing neural responsivity to negative stimuli within key affective circuit elements, including the medial prefrontal and anterior cingulate cortices. These genetically influenced neural response patterns appear to mediate risk for some forms of MDD.
| S-EPMC3091621 | biostudies-literature
Project description:The role of the serotonin transporter promoter linked polymorphism (5HTTLPR) in depression, despite much research, remains unclear. Most studies compare persons with and without depression to each other. We show offspring at high (N = 192) as compared to low (N = 101) familial risk for major depressive disorder were almost four times as likely to have two copies of the short allele at 5HTTLPR, suggesting that incorporation of family history could be helpful in identifying genetic differences.
| S-EPMC4451257 | biostudies-literature
Project description:Importance:Depression often first manifests in adolescence. Thereafter, individual trajectories vary substantially, but it is not known what shapes depression trajectories in youth. Adult studies suggest that genetic risk for schizophrenia, a psychiatric disorder with a neurodevelopmental component, may contribute to an earlier onset of depression. Objective:To test the hypothesis that there are distinct trajectories of depressive symptoms and that genetic liability for neurodevelopmental psychiatric disorders (eg, schizophrenia, attention deficit/hyperactivity disorder [ADHD]), as well as for major depressive disorder (MDD), contribute to early-onset depression. Design, Setting, and Participants:The Avon Longitudinal Study of Parents and Children is an ongoing, prospective, longitudinal, population-based cohort that has been collecting data since September 6, 1990, including data on 7543 adolescents with depressive symptoms at multiple time points. The present study was conducted between November 10, 2017, and August 14, 2018. Main Outcomes and Measures:Trajectories based on self-reported depressive symptoms dichotomized by the clinical cutpoint; MDD, schizophrenia, and ADHD polygenic risk score (PRS) were predictors. Results:In 7543 adolescents with depression data on more than 1 assessment point between a mean (SD) age of 10.64 (0.25) years and 18.65 (0.49) years (3568 [47.3%] male; 3975 [52.7%] female), 3 trajectory classes were identified: persistently low (73.7%), later-adolescence onset (17.3%), and early-adolescence onset (9.0%). The later-adolescence-onset class was associated with MDD genetic risk only (MDD PRS: odds ratio [OR], 1.27; 95% CI, 1.09-1.48; P = .003). The early-adolescence-onset class was also associated with MDD genetic risk (MDD PRS: OR, 1.24; 95% CI, 1.06-1.46; P = .007) but additionally with genetic risk for neurodevelopmental disorders (schizophrenia PRS: OR, 1.22; 95% CI, 1.04-1.43; P = .01; ADHD PRS: OR, 1.32; 95% CI, 1.13-1.54; P < .001) and childhood ADHD (χ21 = 6.837; P = .009) and neurodevelopmental traits (pragmatic language difficulties: OR, 1.31; P = .004; social communication difficulties: OR, 0.68; P < .001). Conclusions and Relevance:The findings of this study appear to demonstrate evidence of distinct depressive trajectories, primarily distinguished by age at onset. The more typical depression trajectory with onset of clinically significant symptoms at age 16 years was associated with MDD genetic risk. The less-common depression trajectory, with a very early onset, was particularly associated with ADHD and schizophrenia genetic risk and, phenotypically, with childhood ADHD and neurodevelopmental traits. Findings are consistent with emerging evidence for a neurodevelopmental component in some cases of depression and suggest that the presence of this component may be more likely when the onset of depression is very early.
| S-EPMC6439821 | biostudies-other
Project description:Trials testing the effect of vitamin D or omega-3 polyunsaturated fatty acid (n3-PUFA) supplementation on major depressive disorder (MDD) reported conflicting findings. These trials were inspired by epidemiological evidence suggesting an inverse association of circulating 25-hydroxyvitamin D (25-OH-D) and n3-PUFA levels with MDD. Observational associations may emerge from unresolved confounding, shared genetic risk, or direct causal relationships. We explored the nature of these associations exploiting data and statistical tools from genomics. Results from genome-wide association studies on 25-OH-D (N = 79 366), n3-PUFA (N = 24 925), and MDD (135 458 cases, 344 901 controls) were applied to individual-level data (>2000 subjects with measures of genotype, DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) lifetime MDD diagnoses and circulating 25-OH-D and n3-PUFA) and summary-level data analyses. Shared genetic risk between traits was tested by polygenic risk scores (PRS). Two-sample Mendelian Randomization (2SMR) analyses tested the potential bidirectional causality between traits. In individual-level data analyses, PRS were associated with the phenotype of the same trait (PRS 25-OH-D p = 1.4e - 20, PRS n3-PUFA p = 9.3e - 6, PRS MDD p = 1.4e - 4), but not with the other phenotypes, suggesting a lack of shared genetic effects. In summary-level data analyses, 2SMR analyses provided no evidence of a causal role on MDD of 25-OH-D (p = 0.50) or n3-PUFA (p = 0.16), or for a causal role of MDD on 25-OH-D (p = 0.25) or n3-PUFA (p = 0.66). Applying genomics tools indicated that shared genetic risk or direct causality between 25-OH-D, n3-PUFA, and MDD is unlikely: unresolved confounding may explain the associations reported in observational studies. These findings represent a cautionary tale for testing supplementation of these compounds in preventing or treating MDD.
| S-EPMC6728377 | biostudies-literature
Project description:Rare or private, biallelic variants in the ABCA3 (ATP-binding cassette transporter A3) gene are the most common monogenic cause of lethal neonatal respiratory failure and childhood interstitial lung disease. Functional characterization of fewer than 10% of over 200 disease-associated ABCA3 variants (majority missense) suggests either disruption of ABCA3 protein trafficking (type I) or of ATPase-mediated phospholipid transport (type II). Therapies remain limited and nonspecific. A scalable platform is required for functional characterization of ABCA3 variants and discovery of pharmacologic correctors. To address this need, we first silenced the endogenous ABCA3 locus in A549 cells with CRISPR/Cas9 genome editing. Next, to generate a parent cell line (A549/ABCA3-/-) with a single recombination target site for genomic integration and stable expression of individual ABCA3 missense variant cDNAs, we used lentiviral-mediated integration of a LoxFAS cassette, FACS, and dilutional cloning. To assess the fidelity of this cell-based model, we compared functional characterization (ABCA3 protein processing, ABCA3 immunofluorescence colocalization with intracellular markers, ultrastructural vesicle phenotype) of two individual ABCA3 mutants (type I mutant, p.L101P; type II mutant, p.E292V) in A549/ABCA3-/- cells and in both A549 cells and primary, human alveolar type II cells that transiently express each cDNA after adenoviral-mediated transduction. We also confirmed pharmacologic rescue of ABCA3 variant-encoded mistrafficking and vesicle diameter in A549/ABCA3-/- cells that express p.G1421R (type I mutant). A549/ABCA3-/- cells provide a scalable, genetically versatile, physiologically relevant functional genomics platform for discovery of variant-specific mechanisms that disrupt ABCA3 function and for screening of potential ABCA3 pharmacologic correctors.
| S-EPMC7528924 | biostudies-literature