[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 SNPs 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 5 significant loci were indels. We further identified 6 additional independent signals, including 3 rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.
Human Molecular Genetics 11/2015; DOI:10.1093/hmg/ddv454 · 6.39 Impact Factor
[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.
European journal of human genetics: EJHG 10/2015; DOI:10.1038/ejhg.2015.222 · 4.35 Impact Factor
[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: High blood pressure, which affects more than 1 billion people worldwide , is a major risk factor for myocardial infarction, stroke and chronic kidney disease. Approximately 9 million deaths each year are attributable to high blood pressure, including >50% of deaths from coronary heart disease and stroke 1,2. High blood pressure is more prevalent in people of East Asian and South Asian ancestry and is a major contributor to their increased risk of stroke and coronary heart disease 3,4. Genome-wide association studies (GWAS) have identified over 50 genetic loci influencing blood pressure in predominantly European populations 5–16. A role for epigenetic mechanisms in blood pressure regulation has also been suggested 17–20. We carried out a GWAS in East Asians and South Asians, as well as Europeans, to seek both cosmopolitan and population-specific genetic effects for five blood pressure phenotypes: systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure, mean arterial pressure (MAP) and hypertension (Supplementary Fig. 1) (ref. 5). We then sought DNA coding and gene regulatory mechanisms, including DNA methylation and gene transcription, to help explain the relationships we observed between sequence variation and blood pressure. RESULTS Genome-wide association and replication testing We used genome-wide association data from 99,994 individuals of East Asian (n = 31,516), European (n = 35,352) and South Asian (n = 33,126) ancestry. Characteristics of the participants and information on the genotyping arrays and imputation are summarized in Supplementary Tables 1–3. Phenotype-specific meta-analysis was carried out separately for East Asian, European and South Asian samples, followed by a meta-analysis across the three ancestral population groups. The trans-ancestry genome-wide association results identified 4,077 variants with P < 1 × 10 −4 against any blood pressure phenotype, distributed among 630 genetic loci. At each locus, we identified the sentinel SNP (the SNP with the lowest P value against any phenotype) and carried out combined analysis with phenotype-specific results from the International Consortium on Blood Pressure (ICBP) GWAS (maximum n = 87,205) (refs. 8,9). This analysis identified 19 previously unreported loci where the sentinel SNP had suggestive evidence for association with blood pressure (P < 1 × 10 −7
[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.
Age 09/2015; 37(5):100. DOI:10.1007/s11357-015-9837-2 · 3.45 Impact Factor
[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.
[Show abstract][Hide abstract] ABSTRACT: Epidemiological studies have reported inverse associations between various single healthy diet indices and lower levels of systemic inflammation, but rarely are they examined in the same sample. The aim of the present study was to investigate the potential relationships between biomarkers of systemic inflammation (C-reactive protein (CRP) and fibrinogen) and overall foods (dietary patterns), single foods (fruits and vegetables), and specific nutritive (antioxidants) and non-nutritive (flavonoids) food components in the same narrow-age cohort of older adults. The dietary intake of 792 participants aged 70 years from the Lothian Birth Cohort 1936 was assessed using a 168-item FFQ. Models were adjusted for age, sex, childhood cognitive ability, lifestyle factors and history of disease. Using logistic regression analyses, CRP (normal
. elevated) was favourably associated (at
< 0·05) with the ‘health-aware’ (low-fat) dietary pattern (unstandardised β = (0·200, OR 0·82, 95 % CI 0·68, 0·99) and fruit intake (unstandardised β = (0·100, OR 0·91, 95 % CI 0·82, 0·99), including flavonoid-rich apples (unstandardised β = (0·456, OR 0·63, 95 % CI 0·439, 0·946). Using linear regression analyses, fibrinogen (continuous) was inversely associated (at
< 0·05) with the Mediterranean dietary pattern (standardised β = (0·100), fruit intake (standardised β = (0·083), and combined fruit and vegetable intake (standardised β = (0·084). We observed no association between food components (antioxidant nutrients or specific flavonoid subclasses) and inflammatory markers. In the present cross-sectional study, nutrient-dense dietary patterns were associated with lower levels of systemic inflammation in older people. The results are consistent with dietary guidelines that promote a balanced diet based on a variety of plant-based foods.
The British journal of nutrition 09/2015; 114(7):1-11. DOI:10.1017/S000711451500210X · 3.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Non-pathological, age-related cognitive decline varies markedly between individuals andplaces significant financial and emotional strain on people, their families and society as a whole.Understanding the differential age-related decline in brain function is critical not only for the development oftherapeutics to prolong cognitive health into old age, but also to gain insight into pathological ageing suchas Alzheimer's disease. The Lothian Birth Cohort of 1936 (LBC1936) comprises a rare group of people forwhom there are childhood cognitive test scores and longitudinal cognitive data during older age, detailedstructural brain MRI, genome-wide genotyping, and a multitude of other biological, psycho-social, andepidemiological data. Synaptic integrity is a strong indicator of cognitive health in the human brain;however, until recently, it was prohibitively difficult to perform detailed analyses of synaptic and axonalstructure in human tissue sections. We have adapted a novel method of tissue preparation at autopsy toallow the study of human synapses from the LBC1936 cohort in unprecedented morphological andmolecular detail, using the high-resolution imaging techniques of array tomography and electronmicroscopy. This allows us to analyze the brain at sub-micron resolution to assess density, proteincomposition and health of synapses. Here we present data from the first donated LBC1936 brain andcompare our findings to Alzheimer's diseased tissue to highlight the differences between healthy andpathological brain ageing.
Our data indicates that compared to an Alzheimer's disease patient, the cognitively normalLBC1936 participant had a remarkable degree of preservation of synaptic structures. However,morphological and molecular markers of degeneration in areas of the brain associated with cognition(prefrontal cortex, anterior cingulate cortex, and superior temporal gyrus) were observed.
Our novel post-mortem protocol facilitates high-resolution neuropathological analysis of the well-characterized LBC1936 cohort, extending phenotyping beyond cognition and in vivo imaging to nowinclude neuropathological changes, at the level of single synapses. This approach offers an unprecedentedopportunity to study synaptic and axonal integrity during ageing and how it contributes to differences in agerelatedcognitive change.
[Show abstract][Hide abstract] ABSTRACT: Objective To explore the multidimensionality of apathy in ALS, To validate the Dimensional Apathy Scale (DAS) in ALS patients and their carers.
Method This was a Scotland- wide questionnaire based study where 83 ALS patients, 75 of their informants and 83 gender-age-education level matched controls were recruited. Control, patient and carer participants completed a standard apathy scale-the Apathy Evaluation scale (AES), the Geriatric Depression Scale-Short form (GDS-15) and the DAS, which is composed of 3 subscales assessing Executive, Emotional and Initiation apathy subtypes. The ALS Functional Rating Scale-Revised (ALSFRS-R) scores were acquired to measure disease related disability.
Results ALS patient (self rated) and carer rated comparison on the DAS showed no significant difference on each of the subscales. There was a significant between-subscale dissociation for both the patients and their carers, F(2,296)=160.30, p<.001. ALS patient (self rated) and control responses to the DAS subscales were found to be significantly different, F(2,328)=13.86, p<.001. Further post-hoc t-tests showed that patients (M=12.5, SD=5.1), compared to controls (M=10.2, SD=4.3), were significantly more impaired on the Initiation subscale, t(64)=3.22, p<.01. Additionally, controls were slightly more Emotionally apathetic (M=8.9, SD=3.2) compared to patients (M=7.7, SD=3.3), t(164)=2.28, p<.05. The psychometrics of the DAS were found to be favourable. The Cronbach's standardized alpha values were high, with the carer (0.90) being slightly higher than the patient (0.86). DAS subscales correlated more highly with the AES compared to the GDS-15, again with that of the carers being slightly higher and better discriminating Emotional apathy against depression. The ALSFRS-R was not significantly correlated with any of the DAS subscales.
Conclusion Using a multidimensional approach to apathy assessment, our study determined that ALS patients showed an apathy profile, characterised by difficulties in initiation of behaviour and cognition. The DAS was found to be a valid and reliable measurement of the dimensions of apathy, independent of disease related disability. Future research will investigate the relationship of these apathy dimensions and cognitive functioning in ALS and further validate the DAS in other neurodegenerative populations.
[Show abstract][Hide abstract] ABSTRACT: Decline in cognitive ability is a core diagnostic criterion for dementia. Knowing the extent of decline requires a baseline score from which change can be reckoned. In the absence of prior cognitive ability scores, vocabulary-based cognitive tests are used to estimate premorbid cognitive ability. It is important that such tests are short yet informative, to maximize information and practicability. The National Adult Reading Test (NART) is commonly used to estimate premorbid intelligence. People are asked to pronounce 50 words ranging from easy to difficult but whether its words conform to a hierarchy is unknown. Five hundred eighty-seven healthy community-dwelling older people with known age 11 IQ scores completed the NART as part of the Lothian Birth Cohort 1936 study. Mokken analysis was used to explore item responses for unidimensional, ordinal, and hierarchical scales. A strong hierarchical scale ("mini-NART") of 23 of the 50 items was identified. These items are invariantly ordered across all ability levels. The validity of the interpretation of this briefer scale's score as an estimate of premorbid ability was examined using the actual age 11 IQ score. The mini-NART accounted for a similar amount of the variance in age 11 IQ as the full NART (NART = 46.5%, mini-NART = 44.8%). The mini-NART is proposed as a useful short clinical tool to estimate prior cognitive ability. The mini-NART has clinical relevance, comprising highly discriminatory, invariantly ordered items allowing for sensitive measurement, and adaptive testing, reducing test administration time, and patient stress. (PsycINFO Database Record
(c) 2015 APA, all rights reserved).
[Show abstract][Hide abstract] ABSTRACT: People with larger brains tend to score higher on tests of general intelligence (g). It is unclear, however, how much variance in intelligence other brain measurements would account for if included together with brain volume in a multivariable model. We examined a large sample of individuals in their seventies (n = 672) who were administered a comprehensive cognitive test battery. Using structural equation modelling, we related six common magnetic resonance imaging-derived brain variables that represent normal and abnormal features—brain volume, cortical thickness, white matter structure, white matter hyperintensity load, iron deposits, and microbleeds—to g and to fluid intelligence. As expected, brain volume accounted for the largest portion of variance (~ 12%, depending on modelling choices). Adding the additional variables, especially cortical thickness (+~ 5%) and white matter hyperintensity load (+~ 2%), increased the predictive value of the model. Depending on modelling choices, all neuroimaging variables together accounted for 18–21% of the variance in intelligence. These results reveal which structural brain imaging measures relate to g over and above the largest contributor, total brain volume. They raise questions regarding which other neuroimaging measures might account for even more of the variance in intelligence.
[Show abstract][Hide abstract] ABSTRACT: Cognitive decline, especially the slowing of information processing speed, is associated with normal ageing. This decline may be due to brain cortico-cortical disconnection caused by age-related white matter deterioration. We present results from a large, narrow age range cohort of generally healthy, community-dwelling subjects in their seventies who also had their cognitive ability tested in youth (age 11 years). We investigate associations between older age brain white matter structure, several measures of information processing speed and childhood cognitive ability in 581 subjects. Analysis of diffusion tensor MRI data using Tract-based Spatial Statistics (TBSS) showed that all measures of information processing speed, as well as a general speed factor composed from these tests (g speed), were significantly associated with fractional anisotropy (FA) across the white matter skeleton rather than in specific tracts. Cognitive ability measured at age 11 years was not associated with older age white matter FA, except for the g speed-independent components of several individual processing speed tests. These results indicate that quicker and more efficient information processing requires global connectivity in older age, and that associations between white matter FA and information processing speed (both individual test scores and g speed), unlike some other aspects of later life brain structure, are generally not accounted for by cognitive ability measured in youth.
Brain Structure and Function 08/2015; DOI:10.1007/s00429-015-1097-5 · 5.62 Impact Factor