Major depressive disorder (MDD) is a highly prevalent disorder with substantial heritability. Heritability has been shown to be substantial and higher in the variant of MDD characterized by recurrent ...episodes of depression. Genetic studies have thus far failed to identify clear and consistent evidence of genetic risk factors for MDD. We conducted a genome-wide association study (GWAS) in two independent datasets. The first GWAS was performed on 1022 recurrent MDD patients and 1000 controls genotyped on the Illumina 550 platform. The second was conducted on 492 recurrent MDD patients and 1052 controls selected from a population-based collection, genotyped on the Affymetrix 5.0 platform. Neither GWAS identified any SNP that achieved GWAS significance. We obtained imputed genotypes at the Illumina loci for the individuals genotyped on the Affymetrix platform, and performed a meta-analysis of the two GWASs for this common set of approximately half a million SNPs. The meta-analysis did not yield genome-wide significant results either. The results from our study suggest that SNPs with substantial odds ratio are unlikely to exist for MDD, at least in our datasets and among the relatively common SNPs genotyped or tagged by the half-million-loci arrays. Meta-analysis of larger datasets is warranted to identify SNPs with smaller effects or with rarer allele frequencies that contribute to the risk of MDD.
Objective
To assess the association between vaginal microbiome (VMB) composition and recurrent early spontaneous preterm birth (sPTB)/preterm prelabour rupture of membranes (PPROM).
Design
Nested ...case–control study.
Setting
UK tertiary referral hospital.
Sample
High‐risk women with previous sPTB/PPROM <34+0 weeks’ gestation who had a recurrence (n = 22) or delivered at ≥37+0 weeks without PPROM (n = 87).
Methods
Vaginal swabs collected between 15 and 22 weeks’ gestation were analysed by 16S rRNA gene sequencing and 16S quantitative PCR.
Main outcome measure
Recurrent early sPTB/PPROM.
Results
Of the 109 high‐risk women, 28 had anaerobic vaginal dysbiosis, with the remainder dominated by lactobacilli (Lactobacillus iners 36/109, Lactobacillus crispatus 23/109, or other 22/109). VMB type and diversity were not associated with recurrence. Women with a recurrence, compared to those without, had a higher median vaginal bacterial load (8.64 versus 7.89 log10 cells/mcl, adjusted odds ratio aOR 1.90, 95% CI 1.01–3.56, P = 0.047) and estimated Lactobacillus concentration (8.59 versus 7.48 log10 cells/mcl, aOR 2.35, (95% CI 1.20–4.61, P = 0.013). A higher recurrence risk was associated with higher median bacterial loads for each VMB type after stratification, although statistical significance was reached only for L. iners domination (aOR 3.44, 95% CI 1.06–11.15, P = 0.040). Women with anaerobic dysbiosis or L. iners domination had a higher median vaginal bacterial load than women with a VMB dominated by L. crispatus or other lactobacilli (8.54, 7.96, 7.63, and 7.53 log10 cells/mcl, respectively).
Conclusions
Vaginal bacterial load is associated with early sPTB/PPROM recurrence. Domination by lactobacilli other than L. iners may protect women from developing high bacterial loads. Future PTB studies should quantify vaginal bacteria and yeasts.
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Increased vaginal bacterial load in the second trimester may be associated with recurrent early spontaneous preterm birth.
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Increased vaginal bacterial load in the second trimester may be associated with recurrent early spontaneous preterm birth.
Various studies have investigated whether single nucleotide polymorphisms (SNPs) in the gene purinergic receptor P2X7 (P2RX7), and rs2230912 specifically, were associated with mood disorders. While ...some studies found positive evidence, a large number of studies reported no significant associations. In a previously published meta-analysis, Feng et al. did not find a significant association and only moderate odds ratios (ORs) in case-control studies. They reported significant findings only for family-based studies. We revisited this finding and conducted a meta-analysis including 8,652 cases and 11,153 controls, adding unpublished results from the Munich Antidepressant Response Signature (MARS) study. We found a significant association between rs2230912 and combined mood disorders (major depressive disorder (MDD) or bipolar disorder (BD)) for the allelic, dominant and heterozygous-disadvantage model, all withstanding the threshold of correction for multiple testing. Stratifying by disorder revealed significant findings for the MDD-subgroup (OR of 1.12 for the allelic model), while the BD-subgroup presented with a lower effect size (OR of 1.05) and no significance. P2RX7 encodes a purinergic receptor which is expressed in the brain and also localized in immune cells.
Animal studies and functional studies will be necessary to enlighten its involvement in the etiology of mood disorders and its applicability for pharmacological purposes.
Mitochondrial dysfunction plays a major role in the pathogenesis of Parkinson disease (PD). Creatine (Cr) is an ergogenic compound that exerts neuroprotective effects in animal models of PD. We ...conducted a 2-year placebo-controlled randomized clinical trial on the effect of Cr in 60 patients with PD. Cr improved patient mood and led to a smaller dose increase of dopaminergic therapy but had no effect on overall Unified Parkinson's Disease Rating Scale scores or dopamine transporter SPECT.
Major mood disorders, which primarily include bipolar disorder and major depressive disorder, are the leading cause of disability worldwide and pose a major challenge in identifying robust risk ...genes. Here, we present data from independent large-scale clinical data sets (including 29 557 cases and 32 056 controls) revealing brain expressed protocadherin 17 (PCDH17) as a susceptibility gene for major mood disorders. Single-nucleotide polymorphisms (SNPs) spanning the PCDH17 region are significantly associated with major mood disorders; subjects carrying the risk allele showed impaired cognitive abilities, increased vulnerable personality features, decreased amygdala volume and altered amygdala function as compared with non-carriers. The risk allele predicted higher transcriptional levels of PCDH17 mRNA in postmortem brain samples, which is consistent with increased gene expression in patients with bipolar disorder compared with healthy subjects. Further, overexpression of PCDH17 in primary cortical neurons revealed significantly decreased spine density and abnormal dendritic morphology compared with control groups, which again is consistent with the clinical observations of reduced numbers of dendritic spines in the brains of patients with major mood disorders. Given that synaptic spines are dynamic structures which regulate neuronal plasticity and have crucial roles in myriad brain functions, this study reveals a potential underlying biological mechanism of a novel risk gene for major mood disorders involved in synaptic function and related intermediate phenotypes.
Dyslexia is one of the most common learning disorders affecting about 5% of all school-aged children. It has been shown that event-related potential measurements reveal differences between dyslexic ...children and age-matched controls. This holds particularly true for mismatch negativity (MMN), which reflects automatic speech deviance processing and is altered in dyslexic children. We performed a whole-genome association analysis in 200 dyslexic children, focusing on MMN measurements. We identified rs4234898, a marker located on chromosome 4q32.1, to be significantly associated with the late MMN component. This association could be replicated in an independent second sample of 186 dyslexic children, reaching genome-wide significance in the combined sample (P = 5.14e-08). We also found an association between the late MMN component and a two-marker haplotype of rs4234898 and rs11100040, one of its neighboring single nucleotide polymorphisms (SNPs). In the combined sample, this marker combination withstands correction for multiple testing (P = 6.71e-08). Both SNPs lie in a region devoid of any protein-coding genes; however, they both show significant association with mRNA-expression levels of SLC2A3 on chromosome 12, the predominant facilitative glucose transporter in neurons. Our results suggest a possible trans-regulation effect on SLC2A3, which might lead to glucose deficits in dyslexic children and could explain their attenuated MMN in passive listening tasks.
Panic disorder (PD) has a lifetime prevalence of 2-4% and heritability estimates of 40%. The contributory genetic variants remain largely unknown, with few and inconsistent loci having been reported. ...The present report describes the largest genome-wide association study (GWAS) of PD to date comprising genome-wide genotype data of 2248 clinically well-characterized PD patients and 7992 ethnically matched controls. The samples originated from four European countries (Denmark, Estonia, Germany, and Sweden). Standard GWAS quality control procedures were conducted on each individual dataset, and imputation was performed using the 1000 Genomes Project reference panel. A meta-analysis was then performed using the Ricopili pipeline. No genome-wide significant locus was identified. Leave-one-out analyses generated highly significant polygenic risk scores (PRS) (explained variance of up to 2.6%). Linkage disequilibrium (LD) score regression analysis of the GWAS data showed that the estimated heritability for PD was 28.0-34.2%. After correction for multiple testing, a significant genetic correlation was found between PD and major depressive disorder, depressive symptoms, and neuroticism. A total of 255 single-nucleotide polymorphisms (SNPs) with p < 1 × 10
were followed up in an independent sample of 2408 PD patients and 228,470 controls from Denmark, Iceland and the Netherlands. In the combined analysis, SNP rs144783209 showed the strongest association with PD (pcomb = 3.10 × 10
). Sign tests revealed a significant enrichment of SNPs with a discovery p-value of <0.0001 in the combined follow up cohort (p = 0.048). The present integrative analysis represents a major step towards the elucidation of the genetic susceptibility to PD.
Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases ...of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case-control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, major depression (MDD) and schizophrenia (SCZ) and a high comorbidity of BOR and MDD, we also analyzed the genetic overlap of BOR with SCZ and MDD. GWAS, gene-based tests and gene-set analyses were performed in 998 BOR patients and 1545 controls. Linkage disequilibrium score regression was used to detect the genetic overlap between BOR and these disorders. Single marker analysis revealed no significant association after correction for multiple testing. Gene-based analysis yielded two significant genes: DPYD (P=4.42 × 10
) and PKP4 (P=8.67 × 10
); and gene-set analysis yielded a significant finding for exocytosis (GO:0006887, P
=0.019; FDR, false discovery rate). Prior studies have implicated DPYD, PKP4 and exocytosis in BIP and SCZ. The most notable finding of the present study was the genetic overlap of BOR with BIP (r
=0.28 P=2.99 × 10
), SCZ (r
=0.34 P=4.37 × 10
) and MDD (r
=0.57 P=1.04 × 10
). We believe our study is the first to demonstrate that BOR overlaps with BIP, MDD and SCZ on the genetic level. Whether this is confined to transdiagnostic clinical symptoms should be examined in future studies.
Although usually thought of as external environmental stressors, a significant heritable component has been reported for measures of stressful life events (SLEs) in twin studies. Method We examined ...the variance in SLEs captured by common genetic variants from a genome-wide association study (GWAS) of 2578 individuals. Genome-wide complex trait analysis (GCTA) was used to estimate the phenotypic variance tagged by single nucleotide polymorphisms (SNPs). We also performed a GWAS on the number of SLEs, and looked at correlations between siblings.
A significant proportion of variance in SLEs was captured by SNPs (30%, p = 0.04). When events were divided into those considered to be dependent or independent, an equal amount of variance was explained for both. This 'heritability' was in part confounded by personality measures of neuroticism and psychoticism. A GWAS for the total number of SLEs revealed one SNP that reached genome-wide significance (p = 4 × 10-8), although this association was not replicated in separate samples. Using available sibling data for 744 individuals, we also found a significant positive correlation of R 2 = 0.08 in SLEs (p = 0.03).
These results provide independent validation from molecular data for the heritability of reporting environmental measures, and show that this heritability is in part due to both common variants and the confounding effect of personality.
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