Whole genome linkage scan of recurrent depressive disorder from the depression network study

Medical Research Council Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, UK.
Human Molecular Genetics (Impact Factor: 6.39). 11/2005; 14(22):3337-45. DOI: 10.1093/hmg/ddi363
Source: PubMed


Genome-wide linkage analysis was carried out in a sample of 497 sib pairs concordant for recurrent major depressive disorder (MDD). There was suggestive evidence for linkage on chromosome 1p36 where the LOD score for female-female pairs exceeded 3 (but reduced to 2.73 when corrected for multiple testing). The region includes a gene, MTHFR, that in previous studies has been associated with depressive symptoms. Two other regions, on chromosomes 12q23.3-q24.11 and 13q31.1-q31.3, showed evidence for linkage with a nominal P < 0.01. The 12q peak overlaps with a region previously implicated by linkage studies of unipolar and bipolar disorders and contains a gene, DAO, that has been associated with both bipolar disorder and schizophrenia. The 13q peak lies within a region previously linked strongly to panic disorder. A fourth modest peak with an LOD of greater than 1 on chromosome 15q lies within a region that showed genome-wide significant evidence of a recurrent depression locus in a previous sib-pair study. Both the 12q and the 15q findings remained significant at genome-wide level when the data from the present study and the previous reports were combined.

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    • "Our results about MTHFR polymorphisms put in evidence a greater genetic vulnerability in women. These findings could be supported by a genome-wide linkage analysis of MDD revealed a female-specific linkage on chromosome 1p36 in the region where the MTHFR gene is located (McGuffin et al., 2005). Our negative data on the putative role of the MTHFR gene in MDD treatment is in line with the literature since to date no association between C677T or A1298C polymorphisms in response to antidepressants has been reported (Mischoulon et al., 2012; Jamerson et al., 2013; Lok et al., 2014; Shen et al., 2014). "
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    ABSTRACT: Methylenetetrahydrofolate reductase (MTHFR) genetic variations have been widely studied in major depressive disorder (MDD) and antidepressants outcome. An interaction with catechol-O-methyltransferase (COMT) has also been proved affecting depression. The aim of this study was to clarify the role of the most commonly studied single nucleotide polymorphisms (SNPs) of MTHFR gene in MDD and in treatment response mechanisms, along with the impact of the interaction with COMT. A total of 613 MDD patients, of whom 389 were classified as having treatment resistant depression (TRD), and 463 controls were enrolled. The A1298C, C677T and COMT Val158Met were genotyped. Genetic data were integrated with a transcriptional level analysis in peripheral blood cells (PBCs) and fibroblasts. The A1298C CC homozygotes were more frequent in MDD patients compared to controls in women, increasing twice the genetic risk to develop depression. Moreover this genotype resulted in epistasis with COMT Met carriers in association with MDD. No significant effects were obtained concerning response to treatment. Transcriptional analyses highlighted a strong correlation between the mRNA levels of MTHFR in fibroblasts and COMT genotypes whereas no significant association with MDD was found. PBCs results revealed relevant influences of environmental factors. We did not measure folate and homocisteine levels. This study showed the involvement of A1298C, Val158Met and their interaction in MDD. The transcriptional analyses supported the participation of COMT in the folate pathway, which partakes in the complex network of gene×gene and gene×environment interactions of MDD etiopathogenesis. Copyright © 2015 Elsevier B.V. All rights reserved.
    Full-text · Article · May 2015 · Journal of Affective Disorders
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    • "For the investigation of familial effects, we used subjects from the DeNt (Depression Network) affected siblings study (Farmer et al. 2004; McGuffin et al. 2005; Breen et al. 2011), which comprises cases of recurrent depression fulfilling DSM-IV and/or ICD-10 criteria of at least moderate severity ascertained from three UK clinical sites (London, Cardiff, Birmingham), four other European sites (Aarhus, Bonn, Dublin, Lausanne) and a site in St Louis, USA. One familial cluster of affected full siblings was identified in each family; in extended families, we used only the sibship including the proband or the sibship with most complete data on AAO and episode frequency. "
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    ABSTRACT: Strategies to dissect phenotypic and genetic heterogeneity of major depressive disorder (MDD) have mainly relied on subphenotypes, such as age at onset (AAO) and recurrence/episodicity. Yet, evidence on whether these subphenotypes are familial or heritable is scarce. The aims of this study are to investigate the familiality of AAO and episode frequency in MDD and to assess the proportion of their variance explained by common single nucleotide polymorphisms (SNP heritability). For investigating familiality, we used 691 families with 2-5 full siblings with recurrent MDD from the DeNt study. We fitted (square root) AAO and episode count in a linear and a negative binomial mixed model, respectively, with family as random effect and adjusting for sex, age and center. The strength of familiality was assessed with intraclass correlation coefficients (ICC). For estimating SNP heritabilities, we used 3468 unrelated MDD cases from the RADIANT and GSK Munich studies. After similarly adjusting for covariates, derived residuals were used with the GREML method in GCTA (genome-wide complex trait analysis) software. Significant familial clustering was found for both AAO (ICC = 0.28) and episodicity (ICC = 0.07). We calculated from respective ICC estimates the maximal additive heritability of AAO (0.56) and episodicity (0.15). SNP heritability of AAO was 0.17 (p = 0.04); analysis was underpowered for calculating SNP heritability of episodicity. AAO and episodicity aggregate in families to a moderate and small degree, respectively. AAO is under stronger additive genetic control than episodicity. Larger samples are needed to calculate the SNP heritability of episodicity. The described statistical framework could be useful in future analyses.
    Full-text · Article · Feb 2015 · Psychological Medicine
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    • "Previous genome-wide association studies (GWAS) have not confirmed the association between polymorphisms in the MTHFR gene or other genes implicated in Hcy metabolism and schizophrenia (Yoshimi et al., 2010; Lencz et al., 2013; Ripke et al., 2013, 2014; Ivorra et al., 2014; Saito et al., 2014) or bipolar disorder (Sklar et al., 2011; Kuo et al., 2014; Mühleisen et al., 2014; Xu et al., 2014) risk. There is only one genome-wide linkage analysis of recurrent depressive disorder providing evidence for linkage on chromosome region 1p36 including the MTHFR gene with the LOD score for female-female pairs estimated at 2.73 (McGuffin et al., 2005). In this regard and taking into account the involvement of Hcy pathway in several physical health impairments, it might be hypothesized that discordant results of GWAS and candidate gene approach studies may originate from genetic heterogeneity across studied populations and various clinical phenotypes including distinct somatic comorbidities that have also been attributed to polymorphisms in the MTHFR gene. "
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    ABSTRACT: Although homocysteine (Hcy) has been widely implicated in the etiology of various physical health impairments, especially cardiovascular diseases, overwhelming evidence indicates that Hcy is also involved in the pathophysiology of schizophrenia and affective disorders. There are several mechanisms linking Hcy to biological underpinnings of psychiatric disorders. It has been found that Hcy interacts with NMDA receptors, initiates oxidative stress, induces apoptosis, triggers mitochondrial dysfunction and leads to vascular damage. Elevated Hcy levels might also contribute to cognitive impairment that is widely observed among patients with affective disorders and schizophrenia. Supplementation of vitamins B and folic acid has been proved to be effective in lowering Hcy levels. There are also studies showing that this supplementation strategy might be beneficial for schizophrenia patients with respect to alleviating negative symptoms. However, there are no studies addressing the influence of add-on therapies with folate and vitamins B on cognitive performance of patients with schizophrenia and affective disorders. In this article, we provide an overview of Hcy metabolism in psychiatric disorders focusing on cognitive correlates and indicating future directions and perspectives.
    Full-text · Article · Sep 2014 · Frontiers in Behavioral Neuroscience
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