Genome-wide association for major depression through age at onset stratification:Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

Background Major depressive disorder (MDD) is a disabling mood disorder and, despite a known heritable component, a large meta-analysis of GWAS revealed no replicable genetic risk variants. Given prior evidence of heterogeneity by age-at-onset (AAO) in MDD, we tested whether genome-wide significant risk variants for MDD could be identified in cases subdivided by AAO. Method Discovery case-control GWASs were performed where cases were stratified using increasing/decreasing AAO-cutoffs; significant SNPs were tested in nine independent replication samples, giving a total sample of 22,158 cases and 133,749 controls for sub-setting. Polygenic score analysis was used to examine if differences in shared genetic risk exists between earlier and adult onset MDD with commonly co-morbid disorders of schizophrenia, bipolar disorder, Alzheimer’s disease, and coronary artery disease. Results We identify one replicated genome-wide significant locus associated with adult-onset (>27 years) MDD (rs7647854, OR=1.16, 95%CI=1.11-1.21, p=5.2x10-11). Using polygenic score analyses, we show that earlier-onset MDD is genetically more similar to schizophrenia and bipolar disorder than adult-onset. Conclusions We demonstrate that using additional phenotype data previously collected by genetic studies to tackle phenotypic heterogeneity in MDD can successfully lead to the discovery of genetic risk factor despite reduced sample size. Furthermore, our results suggest that the genetic susceptibility to MDD differs between adult- and earlier-onset MDD, with earlier-onset cases having a greater genetic overlap with schizophrenia and bipolar disorder

An inflammatory biomarker as a differential predictor of outcome of depression treatment with escitalopram and nortriptyline

Objective: Major depressive disorder has been linked with inflammatory processes, but it is unclear whether individual differences in levels of inflammatory biomarkers could help match patients to treatments that are most likely to be beneficial. The authors tested the hypothesis that C-reactive protein (CRP), a commonly available marker of systemic inflammation, predicts differential response to escitalopram (a serotonin reuptake inhibitor) and nortriptyline (a norepinephrine reuptake inhibitor).SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Copy number variants and therapeutic response to antidepressant medication in major depressive disorder

It would be beneficial to find genetic predictors of antidepressant response to help personalise treatment of major depressive disorder (MDD). Rare copy number variants (CNVs) have been implicated in several psychiatric disorders, including MDD, but their role in antidepressant response has yet to be investigated. CNV data were available for 1565 individuals with MDD from the NEWMEDS (Novel Methods leading to New Medications in Depression and Schizophrenia) consortium with prospective data on treatment outcome with either a serotonergic or noradrenergic antidepressant. No association was seen between the presence of CNV (rare or common), the overall number of CNVs or genomic CNV 'burden' and antidepressant response. Specific CNVs were nominally associated with antidepressant response, including 15q13.3 duplications and exonic NRXN1 deletions. These were associated with poor response to antidepressants. Overall burden of CNVs is unlikely to contribute to personalising antidepressant treatment. Specific CNVs associated with antidepressant treatment require replication and further study to confirm their role in the therapeutic action of antidepressant. © 2014 Macmillan Publishers Limited All rights reserved.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

New insights into the pharmacogenomics of antidepressant response from the GENDEP and STAR∗D studies: Rare variant analysis and high-density imputation

Genome-wide association studies have generally failed to identify polymorphisms associated with antidepressant response. Possible reasons include limited coverage of genetic variants that this study tried to address by exome genotyping and dense imputation. A meta-analysis of Genome-Based Therapeutic Drugs for Depression (GENDEP) and Sequenced Treatment Alternatives to Relieve Depression (STARD) studies was performed at the single-nucleotide polymorphism (SNP), gene and pathway levels. Coverage of genetic variants was increased compared with previous studies by adding exome genotypes to previously available genome-wide data and using the Haplotype Reference Consortium panel for imputation. Standard quality control was applied. Phenotypes were symptom improvement and remission after 12 weeks of antidepressant treatment. Significant findings were investigated in NEWMEDS consortium samples and Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) for replication. A total of 7062 950 SNPs were analyzed in GENDEP (n = 738) and STARD (n = 1409). rs116692768 (P = 1.80e ?08, ITGA9 (integrin ?9)) and rs76191705 (P = 2.59e ?08, NRXN3 (neurexin 3)) were significantly associated with symptom improvement during citalopram/escitalopram treatment. At the gene level, no consistent effect was found. At the pathway level, the Gene Ontology (GO) terms GO: 0005694 (chromosome) and GO: 0044427 (chromosomal part) were associated with improvement (corrected P = 0.007 and 0.045, respectively). The association between rs116692768 and symptom improvement was replicated in PGRN-AMPS (P = 0.047), whereas rs76191705 was not. The two SNPs did not replicate in NEWMEDS. ITGA9 codes for a membrane receptor for neurotrophins and NRXN3 is a transmembrane neuronal adhesion receptor involved in synaptic differentiation. Despite their meaningful biological rationale for being involved in antidepressant effect, replication was partial. Further studies may help in clarifying their role.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Rare and low-frequency coding variants alter human adult height

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of