The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA’s first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.
Genetics; MRI; GWAS; Consortium; Meta-analysis; Multi-site
Objective: We aimed to study the associations between peripheral artery disease (PAD) and ankle-brachial index (ABI) and performance in a range of cognitive domains in nondemented elderly persons. Methods: Data were collected within the Lothian Birth Cohort 1921 and 1936 studies. These are two narrow-age cohorts at age 87 (n = 170) and 73 (n = 748) years. ABI was analyzed as a dichotomous (PAD vs. no PAD) and a continuous measure. PAD was defined as having an ABI less than 0.90. Measures of nonverbal reasoning, verbal declarative memory, verbal fluency, working memory, and processing speed were administered. Both samples were screened for dementia. Results: We observed no significant differences in cognitive performance between persons with or without PAD. However, higher ABI was associated with better general cognition (β = .23, p = .02, R2 change = .05) and processing speed (β = .29, p < .01, R2 change = .08) in the older cohort and better processing speed (β = .12, p < .01, R2 change = .01) in the younger cohort. This was after controlling for age, sex, and childhood mental ability and excluding persons with abnormally high ABI (>1.40) and a history of cardiovascular or cerebrovascular disease. Conclusion: Lower ABI is associated with worse cognitive performance in old age, especially in the oldest old (>85 years), possibly because of long-term exposure to atherosclerotic disease. Interventions targeting PAD in persons free of manifest cardiovascular and cerebrovascular disease may reduce the incidence of cognitive impairment and dementia.
cognition; ankle-brachial index; peripheral artery disease; atherosclerosis; aging
Participants in the Healthy Old People in Edinburgh (HOPE) study (N = 398) were assessed on Raven’s Progressive Matrices and Logical Memory on up to three occasions. Covariates included education, social class, disease and medication status, blood pressure and study outcome. Raven’s score declined linearly with age, whereas decline in Logical Memory was accelerating. There was significant variation in individuals’ rates of decline for Ravens but not Logical Memory. Slope–intercept covariances were not significant. Those who later developed dementia already exhibited lower scores, more so for Logical Memory than Raven’s. Death and study attrition were related to performance, again greater for Logical Memory. Conclusions: The HOPE approach of progressive screening is a feasible and practical method for studying healthy cognitive ageing. As predicted for an initially healthy sample, rates of decline were relatively homogeneous. The hypothesis of differential decline was not supported, nor was a strict interpretation of the hypothesis that cognitive ageing is entirely pathology driven.
Cognitive ageing; Ravens matrices; Logical memory; Physical health
Functional neuroimaging studies report increased right prefrontal cortex (PFC) involvement during verbal memory tasks amongst low-scoring older individuals, compared to younger controls and their higher-scoring contemporaries. Some propose that this reflects inefficient use of neural resources through failure of the left PFC to inhibit non-task-related right PFC activity, via the anterior corpus callosum (CC). For others, it indicates partial compensation – that is, the right PFC cannot completely supplement the failing neural network, but contributes positively to performance. We propose that combining structural and diffusion brain MRI can be used to test predictions from these theories which have arisen from fMRI studies. We test these hypotheses in immediate and delayed verbal memory ability amongst 90 healthy older adults of mean age 73 years. Right hippocampus and left dorsolateral prefrontal cortex (DLPFC) volumes, and fractional anisotropy (FA) in the splenium made unique contributions to verbal memory ability in the whole group. There was no significant effect of anterior callosal white matter integrity on performance. Rather, segmented linear regression indicated that right DLPFC volume was a significantly stronger positive predictor of verbal memory for lower-scorers than higher-scorers, supporting a compensatory explanation for the differential involvement of the right frontal lobe in verbal memory tasks in older age.
Verbal memory; Cognitive ageing; Compensation; MRI; Frontal lobe; Corpus callosum
White matter hyperintensities (WMH) of presumed vascular origin are a common finding in brain magnetic resonance imaging of older individuals and contribute to cognitive and functional decline. It is unknown how WMH form, although white matter degeneration is characterized pathologically by demyelination, axonal loss, and rarefaction, often attributed to ischemia. Changes within normal-appearing white matter (NAWM) in subjects with WMH have also been reported but have not yet been fully characterized. Here, we describe the in vivo imaging signatures of both NAWM and WMH in a large group of community-dwelling older people of similar age using biomarkers derived from magnetic resonance imaging that collectively reflect white matter integrity, myelination, and brain water content. Fractional anisotropy (FA) and magnetization transfer ratio (MTR) were significantly lower, whereas mean diffusivity (MD) and longitudinal relaxation time (T1) were significantly higher, in WMH than NAWM (p < 0.0001), with MD providing the largest difference between NAWM and WMH. Receiver operating characteristic analysis on each biomarker showed that MD differentiated best between NAWM and WMH, identifying 94.6% of the lesions using a threshold of 0.747 × 10−9 m2s−1 (area under curve, 0.982; 95% CI, 0.975–0.989). Furthermore, the level of deterioration of NAWM was strongly associated with the severity of WMH, with MD and T1 increasing and FA and MTR decreasing in NAWM with increasing WMH score, a relationship that was sustained regardless of distance from the WMH. These multimodal imaging data indicate that WMH have reduced structural integrity compared with surrounding NAWM, and MD provides the best discriminator between the 2 tissue classes even within the mild range of WMH severity, whereas FA, MTR, and T1 only start reflecting significant changes in tissue microstructure as WMH become more severe.
Aging; White matter hyperintensities; Normal-appearing white matter; Multimodal MRI
Multifocal basal ganglia T2*-weighted (T2*w) hypointensities, which are believed to arise mainly from vascular mineralization, were recently proposed as a novel MRI biomarker for small vessel disease and ageing. These T2*w hypointensities are typically segmented semi-automatically, which is time consuming, associated with a high intra-rater variability and low inter-rater agreement. To address these limitations, we developed a fully automated, unsupervised segmentation method for basal ganglia T2*w hypointensities. This method requires conventional, co-registered T2*w and T1-weighted (T1w) volumes, as well as region-of-interest (ROI) masks for the basal ganglia and adjacent internal capsule generated automatically from T1w MRI. The basal ganglia T2*w hypointensities were then segmented with thresholds derived with an adaptive outlier detection method from respective bivariate T2*w/T1w intensity distributions in each ROI. Artefacts were reduced by filtering connected components in the initial masks based on their standardised T2*w intensity variance. The segmentation method was validated using a custom-built phantom containing mineral deposit models, i.e. gel beads doped with 3 different contrast agents in 7 different concentrations, as well as with MRI data from 98 community-dwelling older subjects in their seventies with a wide range of basal ganglia T2*w hypointensities. The method produced basal ganglia T2*w hypointensity masks that were in substantial volumetric and spatial agreement with those generated by an experienced rater (Jaccard index = 0.62 ± 0.40). These promising results suggest that this method may have use in automatic segmentation of basal ganglia T2*w hypointensities in studies of small vessel disease and ageing.
•A novel method segmented focal T2*-weighted MRI hypointensities automatically.•The method was validated with MRI of a novel phantom and 98 elderly subjects.•The subject masks from the method and an experienced rater overlapped substantially.•The method is potentially useful for research into small vessel disease and ageing.
Magnetic resonance imaging (MRI); Basal ganglia; Mineralization; Ageing; Focal T2*-weighted MRI hypointensities; Automated segmentation; Outlier detection
Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10−8) with FVC in or near EFEMP1, BMP6, MIR-129-2/HSD17B12, PRDM11, WWOX, and KCNJ2. Two (GSTCD and PTCH1) loci previously associated with spirometric measures were related to FVC. Newly implicated regions were followed-up in samples of African American, Korean, Chinese, and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and pathogenesis of restrictive lung disease.
Elevated glucocorticoid (GC) levels are hypothesized to be deleterious to some brain regions, including white matter (WM). Older age is accompanied by increased between-participant variation in GC levels, yet relationships between WM integrity and cortisol levels in older humans are underexplored. Moreover, it is unclear whether GC-WM associations might be general or pathway specific. We analyzed relationships between salivary cortisol (diurnal and reactive) and general measures of brain WM hyperintensity (WMH) volume, fractional anisotropy (gFA), and mean diffusivity (gMD) in 90 males, aged 73 years. Significant associations were predominantly found between cortisol measures and WMHs and gMD but not gFA. Higher cortisol at the start of a mild cognitive stressor was associated with higher WMH and gMD. Higher cortisol at the end was associated with greater WMHs. A constant or increasing cortisol level during cognitive testing was associated with lower gMD. Tract-specific bases of these associations implicated anterior thalamic radiation, uncinate, and arcuate and inferior longitudinal fasciculi. The cognitive sequelae of these relationships, above other covariates, are a priority for future study.
•We correlated salivary cortisol and brain white matter (WM) measures in older males.•Cortisol was measured diurnally and in reaction to a cognitive challenge.•Diffusion tensor magnetic resonance imaging (fractional anisotropy and mean diffusivity) and total hyperintensity volume measured WM integrity.•WM-cortisol relations were found for mean diffusivity and hyperintensity volume but not fractional anisotropy.•Higher cortisol in response to cognitive stressor denoted lower WM integrity.
Cortisol; Glucocorticoid; White matter; Aging; Brain structure; Tractography
Plasma fibrinogen is an acute phase protein playing an important role in the blood coagulation cascade having strong associations with smoking, alcohol consumption and body mass index (BMI). Genome-wide association studies (GWAS) have identified a variety of gene regions associated with elevated plasma fibrinogen concentrations. However, little is yet known about how associations between environmental factors and fibrinogen might be modified by genetic variation. Therefore, we conducted large-scale meta-analyses of genome-wide interaction studies to identify possible interactions of genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentration. The present study included 80,607 subjects of European ancestry from 22 studies. Genome-wide interaction analyses were performed separately in each study for about 2.6 million single nucleotide polymorphisms (SNPs) across the 22 autosomal chromosomes. For each SNP and risk factor, we performed a linear regression under an additive genetic model including an interaction term between SNP and risk factor. Interaction estimates were meta-analysed using a fixed-effects model. No genome-wide significant interaction with smoking status, alcohol consumption or BMI was observed in the meta-analyses. The most suggestive interaction was found for smoking and rs10519203, located in the LOC123688 region on chromosome 15, with a p value of 6.2×10−8. This large genome-wide interaction study including 80,607 participants found no strong evidence of interaction between genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentrations. Further studies are needed to yield deeper insight in the interplay between environmental factors and gene variants on the regulation of fibrinogen concentrations.
It has been well-established, both by population genetics theory and direct observation in many organisms, that increased genetic diversity provides a survival advantage. However, given the limitations of both sample size and genome-wide metrics, this hypothesis has not been comprehensively tested in human populations. Moreover, the presence of numerous segregating small effect alleles that influence traits that directly impact health directly raises the question as to whether global measures of genomic variation are themselves associated with human health and disease.
We performed a meta-analysis of 17 cohorts followed prospectively, with a combined sample size of 46,716 individuals, including a total of 15,234 deaths. We find a significant association between increased heterozygosity and survival (P = 0.03). We estimate that within a single population, every standard deviation of heterozygosity an individual has over the mean decreases that person’s risk of death by 1.57%.
This effect was consistent between European and African ancestry cohorts, men and women, and major causes of death (cancer and cardiovascular disease), demonstrating the broad positive impact of genomic diversity on human survival.
Electronic supplementary material
The online version of this article (doi:10.1186/s12863-014-0159-7) contains supplementary material, which is available to authorized users.
Heterozygosity; Human; Survival; GWAS
Chronic pain has a strong association with major depressive disorder (MDD), but there is a relative paucity of studies on the association between chronic multisite pain and bipolar disorder (BD). Such studies are required to help elucidate the complex biological and psychological overlap between pain and mood disorders. The aim of this study is to investigate the relationship between chronic multisite pain and mood disorder across the unipolar-bipolar spectrum.
We conducted a cross-sectional study of 149,611 UK Biobank participants. Self-reported depressive and bipolar features were used to categorise participants into MDD and BD groups and a non-mood disordered comparison group. Multinomial logistic regression was used to establish whether there was an association between extent of chronic pain (independent variable) and mood disorder category (dependent variable), using no pain as the referent category, and adjusting for a wide range of potential sociodemographic, lifestyle and comorbidity confounders.
Multisite pain was significantly more prevalent in participants with BD and MDD, for example, 4–7 pain sites: BD 5.8%, MDD 4.5%, and comparison group 1.8% (p < 0.001). A relationship was observed between extent of chronic pain and risk of BD and persisted after adjusting for confounders (relative to individuals with no chronic pain): 2–3 sites RRR of BD 1.84 (95% CI 1.61, 2.11); 4–7 sites RRR of BD 2.39 (95% CI 1.88, 3.03) and widespread pain RRR of BD 2.37 (95% CI 1.73, 3.23). A similar relationship was observed between chronic pain and MDD: 2–3 sites RRR of MDD 1.59 (95% CI 1.54, 1.65); 4–7 sites RRR of MDD 2.13 (95% CI 1.98, 2.30); widespread pain RRR of MDD 1.86 (95% CI 1.66, 2.08).
Individuals who report chronic pain and multiple sites of pain are more likely to have MDD and are at higher risk of BD. These findings highlight an important aspect of comorbidity in MDD and BD and may have implications for understanding the shared neurobiology of chronic pain and mood disorders.
Electronic supplementary material
The online version of this article (doi:10.1186/s12888-014-0350-4) contains supplementary material, which is available to authorized users.
Major depression; Bipolar disorder; Chronic pain; Comorbidity
To examine associations between complexity of main lifetime occupation and cognitive performance in later life.
Occupational complexity ratings for data, people, and things were collected from the Dictionary of Occupational Titles for 1,066 individuals (men = 534, women = 532) in the Lothian Birth Cohort 1936. IQ data were available from mean age 11 years. Cognitive ability data across the domains of general ability, processing speed, and memory were available at mean age 70 years.
General linear model analyses indicated that complexity of work with people and data were associated with better cognitive performance at age 70, after including age 11 IQ, years of education, and social deprivation.
The current findings are supportive of the differential preservation hypotheses that more stimulating environments preserve cognitive ability in later life, although the continued effects into old age are still debated. Studies that have early-life cognitive ability measures are rare, and the current study offers interesting prospects for future research that may further the understanding of successful aging.
Epidemiological studies have shown that weaker grip strength in later life is associated with disability, morbidity, and mortality. Grip strength is a key component of the sarcopenia and frailty phenotypes and yet it is unclear how individual measurements should be interpreted. Our objective was to produce cross-sectional centile values for grip strength across the life course. A secondary objective was to examine the impact of different aspects of measurement protocol.
We combined 60,803 observations from 49,964 participants (26,687 female) of 12 general population studies in Great Britain. We produced centile curves for ages 4 to 90 and investigated the prevalence of weak grip, defined as strength at least 2.5 SDs below the gender-specific peak mean. We carried out a series of sensitivity analyses to assess the impact of dynamometer type and measurement position (seated or standing).
Our results suggested three overall periods: an increase to peak in early adult life, maintenance through to midlife, and decline from midlife onwards. Males were on average stronger than females from adolescence onwards: males’ peak median grip was 51 kg between ages 29 and 39, compared to 31 kg in females between ages 26 and 42. Weak grip strength, defined as strength at least 2.5 SDs below the gender-specific peak mean, increased sharply with age, reaching a prevalence of 23% in males and 27% in females by age 80. Sensitivity analyses suggested our findings were robust to differences in dynamometer type and measurement position.
This is the first study to provide normative data for grip strength across the life course. These centile values have the potential to inform the clinical assessment of grip strength which is recognised as an important part of the identification of people with sarcopenia and frailty.
A balanced t(1;11) translocation which transects the Disrupted in schizophrenia 1 (DISC1) gene shows genome-wide significant linkage for schizophrenia and recurrent major depressive disorder in a single large Scottish family, but genome-wide and exome sequencing-based association studies have not supported a role for DISC1 in psychiatric illness. To explore DISC1 in more detail, we sequenced 528 kb of the DISC1 locus in 653 cases and 889 controls. We report 2,718 validated single nucleotide polymorphisms of which 2,010 have a minor allele frequency of less than 1%. Only 38% of these variants are reported in the 1000 Genomes Project European subset. This suggests that many DISC1 SNPs remain undiscovered and are essentially private. Rare coding variants identified exclusively in patients were found in likely functional protein domains. Significant region-wide association was observed between rs16856199 and recurrent major depressive disorder (P=0.026, unadjusted P=6.3 × 10−5, OR=3.48). This was not replicated in additional recurrent major depression samples (replication P=0.11). Combined analysis of both the original and replication set supported the original association (P=0.0058, OR=1.46). Evidence for segregation of this variant with disease in families was limited to those of rMDD individuals referred from primary care. Burden analysis for coding and non-coding variants gave nominal associations with diagnosis and measures of mood and cognition. Together, these observations are likely to generalise to other candidate genes for major mental illness and may thus provide guidelines for the design of future studies.
General intelligence is an important human quantitative trait that accounts for much of the variation in diverse cognitive abilities. Individual differences in intelligence are strongly associated with many important life outcomes, including educational and occupational attainments, income, health and lifespan1,2. Data from twin and family studies are consistent with a high heritability of intelligence3, but this inference has been controversial. We conducted a genome-wide analysis of 3511 unrelated adults with data on 549 692 SNPs and detailed phenotypes on cognitive traits. We estimate that 40% of the variation in crystallized-type intelligence and 51% of the variation in fluid-type intelligence between individuals is accounted for by linkage disequilibrium between genotyped common SNP markers and unknown causal variants. These estimates provide lower bounds for the narrow-sense heritability of the traits. We partitioned genetic variation on individual chromosomes and found that, on average, longer chromosomes explain more variation. Finally, using just SNP data we predicted approximately 1% of the variance of crystallized and fluid cognitive phenotypes in an independent sample (P = 0.009 and 0.028, respectively). Our results unequivocally confirm that a substantial proportion of individual differences in human intelligence is due to genetic variation, and are consistent with many genes of small effects underlying the additive genetic influences on intelligence.
Intelligence; genetics; GWAS; quantitative trait
The ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) Consortium was set up to analyze brain measures and genotypes from multiple sites across the world to improve the power to detect genetic variants that influence the brain. Diffusion tensor imaging (DTI) yields quantitative measures sensitive to brain development and degeneration, and some common genetic variants may be associated with white matter integrity or connectivity. DTI measures, such as the fractional anisotropy (FA) of water diffusion, may be useful for identifying genetic variants that influence brain microstructure. However, genome-wide association studies (GWAS) require large populations to obtain sufficient power to detect and replicate significant effects, motivating a multi-site consortium effort. As part of an ENIGMA–DTI working group, we analyzed high-resolution FA images from multiple imaging sites across North America, Australia, and Europe, to address the challenge of harmonizing imaging data collected at multiple sites. Four hundred images of healthy adults aged 18–85 from four sites were used to create a template and corresponding skeletonized FA image as a common reference space. Using twin and pedigree samples of different ethnicities, we used our common template to evaluate the heritability of tract-derived FA measures. We show that our template is reliable for integrating multiple datasets by combining results through meta-analysis and unifying the data through exploratory mega-analyses. Our results may help prioritize regions of the FA map that are consistently influenced by additive genetic factors for future genetic discovery studies. Protocols and templates are publicly available at (http://enigma.loni.ucla.edu/ongoing/dti-working-group/).
Diffusion Tensor Imaging (DTI); Imaging genetics; Heritability; Meta-analysis; Multi-site; Reliability
White matter hyperintensities (WMH) are associated with hypertension. We examined interactions between blood pressure (BP), internal carotid artery (ICA) flow velocity parameters and WMH. We obtained BP measurements from 694 community-dwelling subjects at mean ages 69.6 (±0.8) and again at 72.6 (±0.7) years, plus brain MRI and ICA ultrasound at age 73±1 years. Diastolic and mean BP decreased and pulse pressure increased but systolic BP did not change between 70 and 73 years. Multiple linear regression, corrected for vascular disease and risk factors, showed that WMH at age 73 were associated with history of hypertension (β=0.13, p<0.001) and with BP at age 70 (systolic β=0.08, mean β=0.09, diastolic β=0.08, all p<0.05); similar but attenuated associations were seen for BP at age 73. Lower diastolic BP and higher pulse pressure were associated with higher ICA pulsatility index at age 73 (diastolic BP: standardized β, age 70=−0.24, p<0.001; pulse pressure age 70 β=0.19, p<0.001). WMH were associated with higher ICA pulsatility index (β=0.13, p=0.002) after adjusting for BP and correction for multiple testing. Therefore falling diastolic BP and increased pulse pressure are associated with increased ICA pulsatility index, which in turn is associated with WMH. This suggests that hypertension and WMH may either associate indirectly because hypertension increases arterial stiffness which leads to WMH over time, or co-associate through advancing age and stiffer vessels, or both. Reducing vascular stiffness may reduce WMH progression and should be tested in randomised trials, in addition to testing antihypertensive therapy.
blood flow velocity; blood pressure; pulse pressure; white matter hyperintensities; ageing; magnetic resonance imaging
Hippocampal structural integrity is commonly quantified using volumetric measurements derived from brain magnetic resonance imaging (MRI). Previously reported associations with cognitive decline have not been consistent. We investigate hippocampal integrity using quantitative MRI techniques and its association with cognitive abilities in older age.
Participants from the Lothian Birth Cohort 1936 underwent brain MRI at mean age 73 years. Longitudinal relaxation time (T1), magnetization transfer ratio (MTR), fractional anisotropy (FA) and mean diffusivity (MD) were measured in the hippocampus. General factors of fluid-type intelligence (g), cognitive processing speed (speed) and memory were obtained at age 73 years, as well as childhood IQ test results at age 11 years. Amongst 565 older adults, multivariate linear regression showed that, after correcting for ICV, gender and age 11 IQ, larger left hippocampal volume was significantly associated with better memory ability (β = 0.11, p=0.003), but not with speed or g. Using quantitative MRI and after correcting for multiple testing, higher T1 and MD were significantly associated with lower scores of g (β range = −0.11 to −0.14, p<0.001), speed (β range = −0.15 to −0.20, p<0.001) and memory (β range = −0.10 to −0.12, p<0.001). Higher MTR and FA in the hippocampus were also significantly associated with higher scores of g (β range = 0.17 to 0.18, p<0.0001) and speed (β range = 0.10 to 0.15, p<0.0001), but not memory.
Quantitative multi-modal MRI assessments were more sensitive at detecting cognition-hippocampal integrity associations than volumetric measurements, resulting in stronger associations between MRI biomarkers and age-related cognition changes.
Longitudinal Relaxation Times; Diffusion Tensor Imaging; Hippocampus; Cognition; Ageing; Magnetic resonance imaging
Acute hypoglycemia impairs cognitive function in several domains. Executive cognitive function governs organization of thoughts, prioritization of tasks, and time management. This study examined the effect of acute hypoglycemia on executive function in adults with and without diabetes.
RESEARCH DESIGN AND METHODS
Thirty-two adults with and without type 1 diabetes with no vascular complications or impaired awareness of hypoglycemia were studied. Two hyperinsulinemic glucose clamps were performed at least 2 weeks apart in a single-blind, counterbalanced order, maintaining blood glucose at 4.5 mmol/L (euglycemia) or 2.5 mmol/L (hypoglycemia). Executive functions were assessed with a validated test suite (Delis-Kaplan Executive Function). A general linear model (repeated-measures ANOVA) was used. Glycemic condition (euglycemia or hypoglycemia) was the within-participant factor. Between-participant factors were order of session (euglycemia-hypoglycemia or hypoglycemia-euglycemia), test battery used, and diabetes status (with or without diabetes).
Compared with euglycemia, executive functions (with one exception) were significantly impaired during hypoglycemia; lower test scores were recorded with more time required for completion. Large Cohen d values (>0.8) suggest that hypoglycemia induces decrements in aspects of executive function with large effect sizes. In some tests, the performance of participants with diabetes was more impaired than those without diabetes.
Executive cognitive function, which is necessary to carry out many everyday activities, is impaired during hypoglycemia in adults with and without type 1 diabetes. This important aspect of cognition has not received previous systematic study with respect to hypoglycemia. The effect size is large in terms of both accuracy and speed.
Alzheimer's disease patients have deficits in specific cognitive domains, and susceptibility genes for this disease may influence human cognition in nondemented individuals. To evaluate the role of Alzheimer's disease-linked genetic variation on cognition and normal cognitive ageing, we investigated two Scottish cohorts for which assessments in major cognitive domains are available: the Lothian Birth Cohort of 1921 and the Lothian Birth Cohort of 1936, consisting of 505 and 998 individuals, respectively. 158 SNPs from eleven genes were evaluated. Single SNP analyses did not reveal any statistical association after correction for multiple testing. One haplotype from TRAPPC6A was associated with nonverbal reasoning in both cohorts and combined data sets. This haplotype explains a small proportion of the phenotypic variability (1.8%). These findings warrant further investigation as biological modifiers of cognitive ageing.
Lower intelligence is a risk factor for several specific mental disorders, but it is unclear whether it is a risk factor for all mental disorder or whether it is associated with illness severity. We examined the relation between pre-morbid intelligence and risk of hospital admission and total admission rates for the whole range of mental disorders.
Participants were 1,049,663 Swedish men who took tests of intelligence on conscription into military service and were followed up for hospital admissions for mental disorder for a mean of 22.6 years. International Classification of Diseases diagnoses were recorded at discharge from hospital.
Risk of hospital admission for all categories of disorder rose with each point decrease in the nine-point IQ score. For a standard deviation decrease in IQ, age-adjusted hazard ratios (95% CI) were 1.60 (1.55, 1.65) for schizophrenia, 1.49 (1.45, 1.53) for other non-affective psychoses, 1.50 (1.47, 1.51) for mood disorders, 1.51 (1.48, 1.54) for neurotic disorders, 1.60 (1.56, 1.64) for adjustment disorders, 1.75 (1.70, 1.80) for personality disorders, 1.75 (1.73, 1.77) for alcohol-related and 1.85 (1.82, 1.88) for other substance use disorders. Lower intelligence was associated with greater comorbidity. Associations changed little on adjustment for potential confounders. Men with lower intelligence had higher total admission rates, a possible marker of clinical severity.
Lower intelligence is a risk factor for the whole range of mental disorders and for illness severity. Understanding the underlying mechanisms is crucial if we are to find ways to reduce the burden of mental illness.
There is growing evidence of an inverse association between intelligence (IQ) and unintentional injuries.
Analyses are based on a cohort of 1,109,475 Swedish men with IQ measured in early adulthood. Men were followed-up for an average 24 years and hospital admissions for unintentional injury were recorded.
198,133 (17.9%) men had at least one hospital admission for any unintentional injury during follow-up. The most common cause of unintentional injury was falling, followed by road accidents, poisoning, fire and drowning. In addition, 14,637 (1.3%) men had at least one admission for complications of medical care. After adjusting for confounding variables, lower IQ scores were associated with an elevated risk of any unintentional injury (Hazard ratio (95% confidence interval) per standard deviation decrease in IQ: 1.15 (1.14, 1.15)), and of cause-specific injuries other than drowning (poisoning (1.53 (1.49, 1.57)), fire (1.36 (1.31, 1.41)), road traffic accidents (1.25 (1.23, 1.26)), medical complications (1.20 (1.18, 1.22)), and falling (1.17 (1.16, 1.18)). These gradients were stepwise across the full IQ range.
Low IQ scores in early adulthood were associated with a subsequently increased risk of unintentional injury. A greater understanding of mechanisms underlying these associations may provide opportunities and strategies for prevention.
IQ; injury; socioeconomic status; cohort
Lower IQ individuals have an increased risk of psychological disorders, mental health problems, and suicide; similarly, children with low IQ scores are more likely to have behavioural, emotional and anxiety disorders. However, very little is known about the impact of parental IQ on the mental health outcomes of their children.
To determine whether maternal and paternal IQ score is associated with offspring conduct, emotional and attention scores.
Members of 1958 National Child Development Study and their offspring. Of 2,984 parent-offspring pairs, with non-adopted children aged 4+ years, 2,202 pairs had complete data on all variables of interest and were included in the analyses.
Offspring conduct, emotional and attention scores based on Behavioural Problems Index for children aged 4-6 years or the Rutter A scale for children aged 7 and over.
There was little evidence of any association of parental IQ with conduct or emotional problems in younger (aged 4-6) children. However, among children aged 7+, there was strong evidence from age- and sex-adjusted models to support a decrease in conduct, emotional and attention problems in those whose parents had higher IQ scores. These associations were linear across the full IQ range. Individual adjustments for socioeconomic status and child’s own IQ had limited impact while adjustments for Home Observation for Measurement of the Environment (HOME) scores and parental malaise attenuated associations with mother’s IQ but, again, had little impact on associations with father’s IQ. Strong associations were no longer evident in models that simultaneously adjusted for all four potential mediating variables.
Children whose parents score poorly on IQ tests may have an increased risk of conduct, emotional and attention problems. Home environment, parental malaise, and child’s own IQ may have a role in explaining these associations.
There is growing evidence of an association between low intelligence (IQ) and increased risk of assault. However, previous studies are relatively small, do not adjust for socioeconomic status, and have not examined method-specific assaults.
Cox proportional hazards regression was used to explore IQ associations with assault by any means and by four specific methods in a large prospective cohort of 1,120,988 Swedish men. Study members had IQ measured in early adulthood and were well characterised for socioeconomic status in childhood and adulthood. Men were followed-up for an average of 24 years and hospital admissions for injury due to assault were recorded.
16,512 (1.5%) men had at least one hospital admission for injury due to assault by any means during follow-up. The most common assault was during a fight (N=13,144), followed by stabbing (N=1,211), blunt instrument (N=352), and firearms assaults (N=51). After adjusting for confounding variables, lower IQ scores were associated with an elevated risk of hospitalisation for assaults by any means (Hazard ratio (95% confidence interval) per standard deviation decrease in IQ: 1.51 (1.49, 1.54)), and for each of the cause-specific assaults (fight: 1.48 (1.45, 1.51); stabbing: 1.68 (1.58, 1.79); blunt instrument: 1.65 (1.47, 1.85); and firearms: 1.34 (1.00, 1.80)). These gradients were stepwise across the full IQ range.
Low IQ scores in early adulthood were associated with a subsequently increased risk of assault. A greater understanding of mechanisms underlying these associations may provide opportunities and strategies for prevention.
IQ; assault; socioeconomic status; cohort
Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease (CVD), range from 34 to 50%. Genetic variants so far identified by genome-wide association (GWA) studies only explain a small proportion (< 2%) of its variation.
Methods and Results
We conducted a meta-analysis of 28 GWA studies, including more than 90,000 subjects of European ancestry, the first GWA meta-analysis of fibrinogen levels in 7 African Americans studies totaling 8,289 samples, and a GWA study in Hispanic-Americans totaling 1,366 samples. Evaluation for association of SNPs with clinical outcomes included a total of 40,695 cases and 85,582 controls for coronary artery disease (CAD), 4,752 cases and 24,030 controls for stroke, and 3,208 cases and 46,167 controls for venous thromboembolism (VTE). Overall, we identified 24 genome-wide significant (P<5×10−8) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the three structural fibrinogen genes and pathways related to inflammation, adipocytokines and thyrotrophin-releasing hormone signaling. Whereas lead SNPs in a few loci were significantly associated with CAD, the combined effect of all 24 fibrinogen-associated lead SNPs was not significant for CAD, stroke or VTE.
We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and CAD, stroke or VTE.
Fibrinogen; cardiovascular disease; genome-wide association study