[Show abstract][Hide abstract] ABSTRACT: Two themes are emerging regarding the molecular genetic aetiology of intelligence. The first is that intelligence is influenced by many variants and those that are tagged by common single nucleotide polymorphisms account for around 30% of the phenotypic variation. The second, in line with other polygenic traits such as height and schizophrenia, is that these variants are not randomly distributed across the genome but cluster in genes that work together. Less clear is whether the very low range of cognitive ability (intellectual disability) is simply one end of the normal distribution describing individual differences in cognitive ability across a population. Here, we examined 40 genes with a known association with non-syndromic autosomal recessive intellectual disability (NS-ARID) to determine if they are enriched for common variants associated with the normal range of intelligence differences. The current study used the 3511 individuals of the Cognitive Ageing Genetics in England and Scotland (CAGES) consortium. In addition, a text mining analysis was used to identify gene sets biologically related to the NS-ARID set. Gene-based tests indicated that genes implicated in NS-ARID were not significantly enriched for quantitative trait loci (QTL) associated with intelligence. These findings suggest that genes in which mutations can have a large and deleterious effect on intelligence are not associated with variation across the range of intelligence differences.
[Show abstract][Hide abstract] ABSTRACT: Background Several recessive Mendelian disorders are common in Europeans, including cystic fibrosis (CFTR), medium-chain-acyl-Co-A-dehydrogenase deficiency (ACADM), phenylketonuria (PAH) and alpha 1-antitrypsin deficiency (SERPINA1).
Methods In a multicohort study of >19 000 older individuals, we investigated the relevant phenotypes in heterozygotes for these genes: lung function (forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC)) for CFTR and SERPINA1; cognitive measures for ACADM and PAH; and physical capability for ACADM, PAH and SERPINA1.
Results Findings were mostly negative but lung function in SERPINA1 (protease inhibitor (PI) Z allele, rs28929474) showed enhanced FEV1 and FVC (0.13 z-score increase in FEV1 (p=1.7×10−5) and 0.16 z-score increase in FVC (p=5.2×10−8)) in PI-MZ individuals. Height adjustment (a known, strong correlate of FEV1 and FVC) revealed strong positive height associations of the Z allele (1.50 cm increase in height (p=3.6×10−10)).
Conclusions The PI-MZ rare (2%) SNP effect is nearly four times greater than the ‘top’ common height SNP in HMGA2. However, height only partially attenuates the SERPINA1-FEV1 or FVC association (around 50%) and vice versa. Height SNP variants have recently been shown to be positively selected collectively in North versus South Europeans, while the Z allele high frequency is localised to North Europe. Although PI-ZZ is clinically disadvantageous to lung function, PI-MZ increases both height and respiratory function; potentially a balanced polymorphism. Partial blockade of PI could conceivably form part of a future poly-therapeutic approach in very short children. The notion that elastase inhibition should benefit patients with chronic obstructive pulmonary disease may also merit re-evaluation. PI is already a therapeutic target: our findings invite a reconsideration of the optimum level in respiratory care and novel pathway potential for development of agents for the management of growth disorders.
Preview · Article · Feb 2016 · Journal of Medical Genetics
[Show abstract][Hide abstract] ABSTRACT: Background:
Coronary artery disease (CAD) is associated with cognitive decrements and risk of later dementia, but it is not known if shared genetic factors underlie this association. We tested whether polygenic risk for CAD was associated with cognitive ability in community-dwelling cohorts of middle-aged and older adults.
Individuals from Generation Scotland: Scottish Family Health Study (GS:SFHS, N = 9865) and from the Lothian Birth Cohorts of 1921 (LBC1921, N = 517) and 1936 (LBC1936, N = 1005) provided cognitive data and genome-wide genotype data. Polygenic risk profile scores for CAD were calculated for all of the cohorts using the largest available genome-wide association studies (GWAS) data set, the CARDIoGRAM consortium (22 233 cases and 64 762 controls). Polygenic risk profile scores for CAD were then tested for their association with cognitive abilities in the presence and absence of manifest cardiovascular disease.
A meta-analysis of all three cohorts showed a negative association between CAD polygenic risk and fluid cognitive ability (β = -0.022, P = 0.016), verbal intelligence (β = -0.024, P = 0.011) and memory (β = -0.021, P = 0.028).
Increased polygenic risk for CAD is associated with lower cognitive ability in older adults. Common genetic variants may underlie some of the association between age-related cognitive decrements and the risk for CAD.
Full-text · Article · Jan 2016 · International Journal of Epidemiology
[Show abstract][Hide abstract] ABSTRACT: Background:
Information on childhood determinants of frailty or allostatic load in later life is sparse. We investigated whether lower intelligence and greater socioeconomic disadvantage in childhood increased the risk of frailty and higher allostatic load, and explored the mediating roles of adult socioeconomic position, educational attainment and health behaviours.
Participants were 876 members of the Lothian Birth Cohort 1936 whose intelligence was assessed at age 11. At age 70, frailty was assessed using the Fried criteria. Measurements were made of fibrinogen, triglyceride, total and high-density lipoprotein cholesterol, albumin, glycated haemoglobin, C reactive protein, body mass index and blood pressure, from which an allostatic load score was calculated.
In sex-adjusted analyses, lower intelligence and lower social class in childhood were associated with an increased risk of frailty: relative risks (95% CIs) were 1.57 (1.21 to 2.03) for a SD decrease in intelligence and 1.48 (1.12 to 1.96) for a category decrease in social class. In the fully adjusted model, both associations ceased to be significant: relative risks were 1.13 (0.83 to 1.54) and 1.19 (0.86 to 1.61), respectively. Educational attainment had a significant mediating effect. Lower childhood intelligence in childhood, but not social class, was associated with higher allostatic load. The sex-adjusted coefficient for allostatic load for a SD decrease in intelligence was 0.10 (0.07 to 0.14). In the fully adjusted model, this association was attenuated but remained significant (0.05 (0.01 to 0.09)).
Further research will need to investigate the mechanisms whereby lower childhood intelligence is linked to higher allostatic load in later life.
Preview · Article · Dec 2015 · Journal of epidemiology and community health
[Show abstract][Hide abstract] ABSTRACT: Background and purpose:
We assessed cross-sectional and longitudinal relationships between whole brain white matter hyperintensity (WMH) volume and regional cortical thickness.
We measured WMH volume and regional cortical thickness on magnetic resonance imaging at ≈73 and ≈76 years in 351 community-dwelling subjects from the Lothian Birth Cohort 1936. We used multiple linear regression to calculate cross-sectional and longitudinal associations between regional cortical thickness and WMH volume controlling for age, sex, Mini Mental State Examination, education, intelligence quotient at age 11, and vascular risk factors.
We found cross-sectional associations between WMH volume and cortical thickness within and surrounding the Sylvian fissure at 73 and 76 years (rho=-0.276, Q=0.004). However, we found no significant longitudinal associations between (1) baseline WMH volume and change in cortical thickness; (2) baseline cortical thickness and change in WMH volume; or (3) change in WMH volume and change in cortical thickness.
Our results show that WMH volume and cortical thinning both worsen with age and are associated cross-sectionally within and surrounding the Sylvian fissure. However, changes in WMH volume and cortical thinning from 73 to 76 years are not associated longitudinally in these relatively healthy older subjects. The underlying cause(s) of WMH growth and cortical thinning have yet to be fully determined.
[Show abstract][Hide abstract] ABSTRACT: Objectives:
We investigated the correlation between polygenic risk of ischemic stroke (and its subtypes) and cognitive ability in 3 relatively healthy Scottish cohorts: the Lothian Birth Cohort 1936 (LBC1936), the Lothian Birth Cohort 1921 (LBC1921), and Generation Scotland: Scottish Family Health Study (GS).
Polygenic risk scores for ischemic stroke were created in LBC1936 (n = 1005), LBC1921 (n = 517), and GS (n = 6,815) using genome-wide association study summary data from the METASTROKE collaboration. We investigated whether the polygenic risk scores correlate with cognitive ability in the 3 cohorts.
In the largest cohort, GS, polygenic risk of all ischemic stroke, small vessel disease stroke, and large vessel disease stroke, but not cardioembolic stroke, were correlated with both fluid and crystallized cognitive abilities. The highest correlation was between a polygenic risk score for all ischemic stroke and general cognitive ability (r = -0.070, p = 1.95 × 10(-8)). Few correlations were identified in LBC1936 and LBC1921, but a meta-analysis of all 3 cohorts supported the correlation between polygenic risk of ischemic stroke and cognitive ability.
The findings from this study indicate that even in the absence of stroke, being at high polygenic risk of ischemic stroke is associated with lower cognitive ability.
[Show abstract][Hide abstract] ABSTRACT: Genetic determinants of cognition are poorly characterized, and their relationship to genes that confer risk for neurodevelopmental disease is unclear. Here we performed a systems-level analysis of genome-wide gene expression data to infer gene-regulatory networks conserved across species and brain regions. Two of these networks, M1 and M3, showed replicable enrichment for common genetic variants underlying healthy human cognitive abilities, including memory. Using exome sequence data from 6,871 trios, we found that M3 genes were also enriched for mutations ascertained from patients with neurodevelopmental disease generally, and intellectual disability and epileptic encephalopathy in particular. M3 consists of 150 genes whose expression is tightly developmentally regulated, but which are collectively poorly annotated for known functional pathways. These results illustrate how systems-level analyses can reveal previously unappreciated relationships between neurodevelopmental disease-associated genes in the developed human brain, and provide empirical support for a convergent gene-regulatory network influencing cognition and neurodevelopmental disease.
No preview · Article · Dec 2015 · Nature Neuroscience
[Show abstract][Hide abstract] ABSTRACT: Objectives The observed associations between smoking and functional measures at older ages are vulnerable to bias and confounding. Mendelian randomisation (MR) uses genotype as an instrumental variable to estimate unconfounded causal associations. We conducted a meta-analysis of the observational associations and implemented an MR approach using the smoking-related single nucleotide polymorphism rs16969968 to explore their causal nature.
Setting 9 British cohorts belonging to the HALCyon collaboration.
Participants Individual participant data on N=26 692 individuals of European ancestry (N from earliest phase analysed per study) of mean ages 50–79 years were available for inclusion in observational meta-analyses of the primary outcomes.
Primary outcomes Physical capability, cognitive capability and cognitive decline. The smoking exposures were cigarettes per day, current versus ex-smoker, current versus never smoker and ever versus never smoker.
Results In observational analyses current and ever smoking were generally associated with poorer physical and cognitive capability. For example, current smokers had a general fluid cognition score which was 0.17 z-score units (95% CI −0.221 to −0.124) lower than ex-smokers in cross-sectional analyses. Current smokers had a walk speed which was 0.25 z-score units lower than never smokers (95% CI −0.338 to −0.170). An MR instrumental variable approach for current versus ex-smoker and number of cigarettes smoked per day produced CIs which neither confirmed nor refuted the observational estimates. The number of genetic associations stratified by smoking status were consistent with type I error.
Conclusions Our observational analysis supports the hypothesis that smoking is detrimental to physical and cognitive capability. Further studies are needed for a suitably powered MR approach.
[Show abstract][Hide abstract] ABSTRACT: Lung function measures are used in the diagnosis of chronic obstructive pulmonary disease. In 38,199 European ancestry individuals, we studied genome-wide association of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC with 1000 Genomes Project (phase 1)-imputed genotypes and followed up top associations in 54,550 Europeans. We identify 14 novel loci (P<5 × 10-8) in or near ENSA, RNU5F-1, KCNS3, AK097794, ASTN2, LHX3, CCDC91, TBX3, TRIP11, RIN3, TEKT5, LTBP4, MN1 and AP1S2, and two novel signals at known loci NPNT and GPR126, providing a basis for new understanding of the genetic determinants of these traits and pulmonary diseases in which they are altered.
Full-text · Article · Dec 2015 · Nature Communications
[Show abstract][Hide abstract] ABSTRACT: Individuals with exceptional longevity and their offspring have significantly larger high-density lipoprotein concentrations (HDL-C) particle sizes due to the increased homozygosity for the I405V variant in the cholesteryl ester transfer protein (CETP) gene. In this study, we investigate the association of CETP and HDL-C further to identify novel, independent CETP variants associated with HDL-C in humans.Methods:We performed a meta-analysis of HDL-C within the CETP region using 59,432 individuals imputed with 1000 Genomes data. We performed replication in an independent sample of 47,866 individuals and validation was done by Sanger sequencing.Results:The meta-analysis of HDL-C within the CETP region identified five independent variants, including an exonic variant and a common intronic insertion. We replicated these 5 variants significantly in an independent sample of 47,866 individuals. Sanger sequencing of the insertion within a single family confirmed segregation of this variant. The strongest reported association between HDL-C and CETP variants, was rs3764261; however, after conditioning on the five novel variants we identified the support for rs3764261 was highly reduced (βunadjusted=3.179 mg/dl (P value=5.25×10−509), βadjusted=0.859 mg/dl (P value=9.51×10−25)), and this finding suggests that these five novel variants may partly explain the association of CETP with HDL-C. Indeed, three of the five novel variants (rs34065661, rs5817082, rs7499892) are independent of rs3764261.Conclusions:The causal variants in CETP that account for the association with HDL-C remain unknown. We used studies imputed to the 1000 Genomes reference panel for fine mapping of the CETP region. We identified and validated five variants within this region that may partly account for the association of the known variant (rs3764261), as well as other sources of genetic contribution to HDL-C.
[Show abstract][Hide abstract] ABSTRACT: Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration.
These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage
of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000
Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on
the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified
41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals
on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent
signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.
Full-text · Article · Nov 2015 · Human Molecular Genetics
[Show abstract][Hide abstract] ABSTRACT: 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.European Journal of Human Genetics advance online publication, 21 October 2015; doi:10.1038/ejhg.2015.222.
No preview · Article · Oct 2015 · European journal of human genetics: EJHG
[Show abstract][Hide abstract] ABSTRACT: Inbreeding depression refers to lower fitness among offspring of genetic relatives. This reduced fitness is caused by the inheritance of two identical chromosomal segments (autozygosity) across the genome, which may expose the effects of (partially) recessive deleterious mutations. Even among outbred populations, autozygosity can occur to varying degrees due to cryptic relatedness between parents. Using dense genome-wide single-nucleotide polymorphism (SNP) data, we examined the degree to which autozygosity associated with measured cognitive ability in an unselected sample of 4854 participants of European ancestry. We used runs of homozygosity—multiple homozygous SNPs in a row—to estimate autozygous tracts across the genome. We found that increased levels of autozygosity predicted lower general cognitive ability, and estimate a drop of 0.6 s.d. among the offspring of first cousins (P=0.003–0.02 depending on the model). This effect came predominantly from long and rare autozygous tracts, which theory predicts as more likely to be deleterious than short and common tracts. Association mapping of autozygous tracts did not reveal any specific regions that were predictive beyond chance after correcting for multiple testing genome wide. The observed effect size is consistent with studies of cognitive decline among offspring of known consanguineous relationships. These findings suggest a role for multiple recessive or partially recessive alleles in general cognitive ability, and that alleles decreasing general cognitive ability have been selected against over evolutionary time.
[Show abstract][Hide abstract] ABSTRACT: We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 x 10(-11) to 5.0 x 10(-21)). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 x 10(-6)). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.
[Show abstract][Hide abstract] ABSTRACT: Several studies have reported associations between brain iron deposits and cognitive status, and cardiovascular and neurodegenerative diseases in older individuals, but the mechanisms underlying these associations remain unclear. We explored the associations between regional brain iron deposits and different factors of cognitive ability (fluid intelligence, speed and memory) in a large sample (n = 662) of individuals with a mean age of 73 years. Brain iron deposits in the corpus striatum were extracted automatically. Iron deposits in other parts of the brain (i.e., white matter, thalamus, brainstem and cortex), brain tissue volume and white matter hyperintensities (WMH) were assessed separately and semi-automatically. Overall, 72.8 % of the sample had iron deposits. The total volume of iron deposits had a small but significant negative association with all three cognitive ability factors in later life (mean r = -0.165), but no relation to intelligence in childhood (r = 0.043, p = 0.282). Regression models showed that these iron deposit associations were still present after control for a variety of vascular health factors, and were separable from the association of WMH with cognitive ability. Iron deposits were also associated with cognition across the lifespan, indicating that they are relevant for cognitive ability only at older ages. Iron deposits might be an indicator of small vessel disease that affects the neuronal networks underlying higher cognitive functioning.
[Show abstract][Hide abstract] ABSTRACT: Extraversion is a relatively stable and heritable personality trait associated with numerous psychosocial, lifestyle and health outcomes. Despite its substantial heritability, no genetic variants have been detected in previous genome-wide association (GWA) studies, which may be due to relatively small sample sizes of those studies. Here, we report on a large meta-analysis of GWA studies for extraversion in 63,030 subjects in 29 cohorts. Extraversion item data from multiple personality inventories were harmonized across inventories and cohorts. No genome-wide significant associations were found at the single nucleotide polymorphism (SNP) level but there was one significant hit at the gene level for a long non-coding RNA site (LOC101928162). Genome-wide complex trait analysis in two large cohorts showed that the additive variance explained by common SNPs was not significantly different from zero, but polygenic risk scores, weighted using linkage information, significantly predicted extraversion scores in an independent cohort. These results show that extraversion is a highly polygenic personality trait, with an architecture possibly different from other complex human traits, including other personality traits. Future studies are required to further determine which genetic variants, by what modes of gene action, constitute the heritable nature of extraversion.