White matter hyperintensities (WMH) of presumed vascular origin increase the risk of stroke and dementia. Despite strong WMH heritability, few gene associations have been identified. Relevant ...experimental models may be informative.
We tested the associations between genes that were differentially expressed in brains of young spontaneously hypertensive stroke-prone rats and human WMH (using volume and visual score) in 621 subjects from the Lothian Birth Cohort 1936 (LBC1936). We then attempted replication in 9361 subjects from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE). We also tested the subjects from LBC1936 for previous genome-wide WMH associations found in subjects from CHARGE.
Of 126 spontaneously hypertensive stroke-prone rat genes, 10 were nominally associated with WMH volume or score in subjects from LBC1936, of which 5 (AFP, ALB, GNAI1, RBM8a, and MRPL18) were associated with both WMH volume and score (P<0.05); 2 of the 10 (XPNPEP1, P=6.7×10(-5); FARP1, P=0.024) plus another spontaneously hypertensive stroke-prone rat gene (USMG5, P=0.00014), on chromosomes 10, 13, and 10 respectively, were associated with WMH in subjects from CHARGE. Gene set enrichment showed significant associations for downregulated spontaneously hypertensive stroke-prone rat genes with WMH in humans. In subjects from LBC1936, we replicated CHARGE's genome-wide WMH associations on chromosomes 17 (TRIM65 and TRIM47) and, for the first time, 1 (PMF1).
Despite not passing multiple testing thresholds individually, these genes collectively are relevant to known WMH associations, proposed WMH mechanisms, or dementia: associations with Alzheimer's disease, late-life depression, ATP production, osmotic regulation, neurodevelopmental abnormalities, and cognitive impairment. If replicated further, they suggest a multifactorial nature for WMH and argue for more consideration of vascular contributions to dementia.
Seasonal rhythms are endogenous timing mechanisms that allow animals living at temperate latitudes to synchronize their physiology to the seasons. Human viral respiratory disease is prevalent in the ...winter at temperate latitudes, but the role of endogenous mechanisms in these recurring annual patterns is unclear. The Common Cold Project is a repository of data describing the experimental viral challenge of 1,337 participants across the seasons of the year. We report a secondary analysis of these data to investigate if susceptibility to the common cold is associated with day length. The majority of the participants (78%) showed signs of infection but only 32% developed clinical signs of disease, and the probability of infection was significantly higher in longer day lengths (summer), but the disease was more likely in short (winter) day lengths. The persistence of winter disease patterns in experimental conditions supports the role of endogenous seasonality in human susceptibility to viral infection.
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•Outbreaks of viral respiratory disease recur in winter in the northern hemisphere•In controlled experiments, common cold infection was more likely in summer•Infection was more likely to progress to the development of cold in winter•Innate seasonality of human immunity could affect the prevalence of the common cold
Chronobiology; Virology
Three single nucleotide polymorphisms (SNPs) were recently found to be associated with activated partial thromboplastin time (aPTT). Because shortened aPTT levels have been observed in patients ...experiencing venous thrombosis (VT), we investigated the effects of these 3 aPTT-associated SNPs, rs2731672, rs9898, and rs710446, on the risk of VT in a sample of 1110 healthy patients and 1542 patients with VT. Among the 3 tested SNPs, only rs710446 was associated with VT risk; the rs710446-C allele was associated with an increased risk of VT (odds ratio 1.196, 95% confidence interval 1.071-1.336, P = .0012). This association also was observed in an independent sample of 590 controls and 596 patients (odds ratio 1.171, 95% confidence interval 0.889-1.541, P = .059). We also confirmed that the rs710446-C allele was associated with decreased aPTT levels, making this nonsynonymous Ile581Thr variant a new genetic risk factor for VT.
Low von Willebrand factor (VWF) levels are associated with bleeding symptoms and are a diagnostic criterion for von Willebrand disease, the most common inherited bleeding disorder. To date, it is ...unclear which genetic loci are associated with reduced VWF levels. Therefore, we conducted a meta-analysis of genome-wide association studies to identify genetic loci associated with low VWF levels. For this meta-analysis, we included 31 149 participants of European ancestry from 11 community-based studies. From all participants, VWF antigen (VWF:Ag) measurements and genome-wide single-nucleotide polymorphism (SNP) scans were available. Each study conducted analyses using logistic regression of SNPs on dichotomized VWF:Ag measures (lowest 5% for blood group O and non-O) with an additive genetic model adjusted for age and sex. An inverse-variance weighted meta-analysis was performed for VWF:Ag levels. A total of 97 SNPs exceeded the genome-wide significance threshold of 5 × 10(-8) and comprised five loci on four different chromosomes: 6q24 (smallest P-value 5.8 × 10(-10)), 9q34 (2.4 × 10(-64)), 12p13 (5.3 × 10(-22)), 12q23 (1.2 × 10(-8)) and 13q13 (2.6 × 10(-8)). All loci were within or close to genes, including STXBP5 (Syntaxin Binding Protein 5) (6q24), STAB5 (stabilin-5) (12q23), ABO (9q34), VWF (12p13) and UFM1 (ubiquitin-fold modifier 1) (13q13). Of these, UFM1 has not been previously associated with VWF:Ag levels. Four genes that were previously associated with VWF levels (VWF, ABO, STXBP5 and STAB2) were also associated with low VWF levels, and, in addition, we identified a new gene, UFM1, that is associated with low VWF levels. These findings point to novel mechanisms for the occurrence of low VWF levels.
The identification of biomarkers of transition from the at-risk mental state (ARMS) to psychotic disorder is important because early treatment of psychosis is associated with improved outcome. ...Increasing evidence points to an inflammatory contribution to psychosis. We questioned whether raised levels of plasma inflammatory markers predict transition from ARMS to psychotic disorder and whether any such predictors could be reduced by omega-3 (ω-3) polyunsaturated fatty acids (PUFAs).
We measured the levels of 40 neuroinflammation biomarkers using a commercially available immunoassay kit. Firstly, we compared inflammatory markers in subjects in the ARMS who transitioned to psychotic disorder (n = 11) compared to subjects who did not (n = 28). Then we compared inflammatory markers in all subjects before and after ω-3 PUFA treatment (n = 40).
Our data provides preliminary evidence that elevations in the baseline plasma levels of the inflammatory marker IL12/IL23p40 are associated with transition from ARMS to psychotic disorder. IL12/IL23p40 levels did not change following 12 weeks administration of ω-3 PUFAs. These findings provide evidence that elevated plasma IL12/IL23p40 is a potential biomarker of increased risk for transition to psychotic disorder.
Further studies are required to confirm and extend this finding. Our results do not provide support for the possibility that administration of ω-3 PUFAs act to reduced transition to psychotic disorder by reducing blood levels of IL12/IL23p40.
ClinicalTrials.gov, a service of the U.S. National Institutes of Health, Identifier: NCT00396643 , last updated December 20, 2007. Retrospectively registered.
Differences in genomic structure between individuals are ubiquitous features of human genetic variation. Specific copy number variants (CNVs) have been associated with susceptibility to numerous ...complex psychiatric disorders, including attention-deficit-hyperactivity disorder, autism-spectrum disorders and schizophrenia. These disorders often display co-morbidity with low intelligence. Rare chromosomal deletions and duplications are associated with these disorders, so it has been suggested that these deletions or duplications may be associated with differences in intelligence. Here we investigate associations between large (≥500kb), rare (<1% population frequency) CNVs and both fluid and crystallized intelligence in community-dwelling older people. We observe no significant associations between intelligence and total CNV load. Examining individual CNV regions previously implicated in neuropsychological disorders, we find suggestive evidence that CNV regions around SHANK3 are associated with fluid intelligence as derived from a battery of cognitive tests. This is the first study to examine the effects of rare CNVs as called by multiple algorithms on cognition in a large non-clinical sample, and finds no effects of such variants on general cognitive ability.
Sleep disruption is a common feature of neuropsychiatric disorders (NPDs). Chronotype (morning/evening person) is a behavioural indicator of underlying circadian rhythm. Our research focuses on these ...phenotypes because the evening chronotype has been linked to increased risk of NPDs (autism spectrum disorder, attention deficit hyperactivity disorder, bipolar disorder, insomnia, major depressive disorder and schizophrenia). Genome-wide association studies indicate that these phenotypes are highly polygenic with many risk variants mapping to non-coding regions and are likely to functionally affect gene expression.
We used Mendelian randomisation (MR) to explore the causal role of gene expression alterations (exposure) on NPD risk and chronotype (outcome(s)). We used MR in conjunction with colocalization, a method used to test if two traits (gene expression and phenotype) are caused by a shared variant in a genomic region.
One hundred and seventy-five significant causal associations were identified through MR, of which twelve passed colocalization analysis. Six of the twelve associated expression quantitative trait loci (eQTL)-gene pairs were blood-mediated and nine of the twelve were associated with schizophrenia. The analysis validated the association of several genes with different phenotypes (RP111-890B15-schizophrenia, GPN3-schizophrenia, SNX19-schizophrenia, FADS2-bipolar disorder) and identified a number of eQTLs (rs3751033, rs968567, rs4968646, rs3743138, rs7535162, rs17128077, rs11979881) not previously reported in the literature as associated with these phenotypes.
Overall, MR and colocalization found evidence for causal associations that link changes in gene expression levels to NPDs and chronotype.
Abstract A genome-wide search for genetic variants influencing the brain's white matter integrity in old age was conducted in the Lothian Birth Cohort 1936 (LBC1936). At ∼73 years of age, members of ...the LBC1936 underwent diffusion MRI, from which 12 white matter tracts were segmented using quantitative tractography, and tract-averaged water diffusion parameters were determined (n = 668). A global measure of white matter tract integrity, gFA , derived from principal components analysis of tract-averaged fractional anisotropy measurements, accounted for 38.6% of the individual differences across the 12 white matter tracts. A genome-wide search was performed with gFA on 535 individuals with 542,050 single nucleotide polymorphisms (SNPs). No single SNP association was genome-wide significant (all p > 5 × 10−8 ). There was genome-wide suggestive evidence for two SNPs, one in ADAMTS18 ( p = 1.65 × 10−6 ), which is related to tumor suppression and hemostasis, and another in LOC388630 ( p = 5.08 × 10−6 ), which is of unknown function. Although no gene passed correction for multiple comparisons in single gene-based testing, biological pathways analysis suggested evidence for an over-representation of neuronal transmission and cell adhesion pathways relating to gFA.
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