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George Davey Smith

Publications and source records attributed to George Davey Smith.

At least 19 recordsLinked to original sources
PubMed2026

Robust inference and correlates from genetic associations with personality.

Personality traits describe stable differences in how people think, feel and behave, and how they interact with and experience their social and physical environments1,2. Many questions remain unanswered about associations between DNA and personality traits, such as their robustness, their generalizability and the biological and social pathways through which they act. Here we meta-analyse data across 46 cohorts comprising 611,037 to 1.14 million participants with European-like and African-like genomes for genome-wide association studies (GWAS) of the Big Five personality traits (extraversion, agreeableness, conscientiousness, neuroticism and openness to experience), and data from up to 50,725 participants for within-family GWAS. We identify 1,260 lead genetic variants associated with personality, including 824 novel variants3. Common genetic variants explain a moderate 4.8-9.3% of the variance in measures of each trait, and 9.3-13.3% among instruments with typical measurement reliability. Genetic associations with personality are highly consistent but not identical across geography, reporter (self versus close other), age group and measurement instrument, and we find minimal spousal assortment for personality in recent history. In contrast to many other social and behavioural traits4,5, within-family GWAS and polygenic index analyses indicate that genetic associations with personality are minimally confounded by the shared family environment. Polygenic prediction, genetic correlation and Mendelian randomization analyses indicate that personality traits have widespread, potentially causal associations with consequential behaviours and life outcomes. Overall, we find that the genetic architecture of personality is robustly generalizable, minimally confounded and widely relevant to human experience.

Journal Article↗
PubMed2026

Can we identify people with Alzheimer's disease from examination of the eye? A bidirectional Mendelian randomization (MR) study.

BACKGROUND: Neurodegeneration in Alzheimer's disease (AD) is thought to be driven by amyloid-beta and tau deposition in the cerebral vasculature and brain. As the eye is an extension of the central nervous system, this study aimed to determine which neurovascular and neuroretinal changes in the eye are caused by AD rather than associations of the disease. METHODS: Bidirectional two-sample univariable and multivariable Mendelian randomization (MR) methods were applied. Instrumental variables were derived from genome-wide association studies (GWAS) of AD and the following ocular features: thickness measurements of central macula (MT), retinal nerve fibre layer (mRNFL), ganglion cell-inner plexiform layer (mGCIPL), outer nuclear layer (ONL), inner segment layer (IS), and outer segment (OS) from macular region OCT scans; arteriolar tortuosity (AT), venular tortuosity (VT), venular width (VW), fractal dimension (FD), vertical cup-to-disc ratio (VCDR), optic cup area (OCA), and optic disc area (ODA) derived from other imaging methods. RESULTS: There was strong evidence that genetic liability to AD affected the retinal vasculature by specifically increasing AT (β = 0.007;95%CI=0.002,0.011;p-value=0.005) in UK Biobank participants (n=52,798). AD may influence the mRNFL (β=-0.047,95%CI=-0.119,0.023,p-value=0.18) and mGCIPL (β=-0.061;95%CI=-0.14,0.025,p-value=0.16) of the inner retina and OS layer (β = 0.044;95%CI=-0.0001,0.08;p-value=0.05) but the evidence was weak. Multivariable MR analysis showed that a causal relationship between optic disc area and AD (OR=0.76;95%CI=0.62,0.93,p-value=0.009) was probably mediated by refractive error. CONCLUSION: Early cerebrovascular signs of AD may be detected by examination of the eye. Further investigation is required to determine the clinical utility of eye screening for dementia.

Humans↗
PubMed2025

No More Free Lunch: Challenges to Mendelian Randomization Due to Sample Selection and Complex Methods.

Mendelian randomization (MR) is increasingly used in epidemiological studies to investigate causal relationships. MR depends on 3 fundamental instrumental variable assumptions: relevance, independence, and exclusion restriction. Studies often assume that MR mitigates bias from confounding due to the random allocation of genetic variants at conception. In this perspective, using causal directed acyclic graphs, we discuss several scenarios where biases in MR analyses may arise due to the nature of the data or methods being used. These include (1) collider bias due to the nonrandom selection of participants into study populations used for conducting genome-wide association studies (GWAS), (2) indirect genetic effects arising from population-based GWAS rather than within-family studies, and (3) collider bias due to gene-environment interaction effects on the exposure in nonlinear MR analyses. We provide practical considerations for examining and reducing these biases in MR analyses.

Humans↗
PubMed2025

Genome-wide association study of long COVID.

Infections can lead to persistent symptoms and diseases such as shingles after varicella zoster or rheumatic fever after streptococcal infections. Similarly, severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infection can result in long coronavirus disease (COVID), typically manifesting as fatigue, pulmonary symptoms and cognitive dysfunction. The biological mechanisms behind long COVID remain unclear. We performed a genome-wide association study for long COVID including up to 6,450 long COVID cases and 1,093,995 population controls from 24 studies across 16 countries. We discovered an association of FOXP4 with long COVID, independent of its previously identified association with severe COVID-19. The signal was replicated in 9,500 long COVID cases and 798,835 population controls. Given the transcription factor FOXP4's role in lung physiology and pathology, our findings highlight the importance of lung function in the pathophysiology of long COVID.

Humans↗
PubMed2016

Gene co-expression analysis identifies brain regions and cell types involved in migraine pathophysiology: a GWAS-based study using the Allen Human Brain Atlas.

Migraine is a common disabling neurovascular brain disorder typically characterised by attacks of severe headache and associated with autonomic and neurological symptoms. Migraine is caused by an interplay of genetic and environmental factors. Genome-wide association studies (GWAS) have identified over a dozen genetic loci associated with migraine. Here, we integrated migraine GWAS data with high-resolution spatial gene expression data of normal adult brains from the Allen Human Brain Atlas to identify specific brain regions and molecular pathways that are possibly involved in migraine pathophysiology. To this end, we used two complementary methods. In GWAS data from 23,285 migraine cases and 95,425 controls, we first studied modules of co-expressed genes that were calculated based on human brain expression data for enrichment of genes that showed association with migraine. Enrichment of a migraine GWAS signal was found for five modules that suggest involvement in migraine pathophysiology of: (i) neurotransmission, protein catabolism and mitochondria in the cortex; (ii) transcription regulation in the cortex and cerebellum; and (iii) oligodendrocytes and mitochondria in subcortical areas. Second, we used the high-confidence genes from the migraine GWAS as a basis to construct local migraine-related co-expression gene networks. Signatures of all brain regions and pathways that were prominent in the first method also surfaced in the second method, thus providing support that these brain regions and pathways are indeed involved in migraine pathophysiology.

Atlases as Topic↗
PubMed2007

Prevalence and functionality of paucimorphic and private MC4R mutations in a large, unselected European British population, scanned by meltMADGE.

Identification of unknown mutations has remained laborious, expensive, and only viable for studies of selected cases. Population-based "reference ranges" of rarer sequence diversity are not available. However, the research and diagnostic interpretation of sequence variants depends on such information. Additionally, this is the only way to determine prevalence of severe, moderate, and silent mutations and is also relevant to the development of screening programs. We previously described a system, meltMADGE, suitable for mutation scanning at the population level. Here we describe its application to a population-based study of MC4R (melanocortin 4 receptor) mutations, which are associated with obesity. We developed nine assays representing MC4R and examined a population sample of 1,100 subjects. Two "paucimorphisms" were identified (c.307G>A/p.Val103Ile in 27 subjects and c.-178A>C in 22 subjects). Neither exhibited any anthropometric effects, whereas there would have been >90% power to detect a body mass index (BMI) effect of 0.5 kg/m(2) at P=0.01. Two "private" variants were also identified. c.335C>T/p.Thr112Met has been previously described and appears to be silent. A novel variant, c.260C>A/p.Ala87Asp, was observed in a subject with a BMI of 31.5 kg/m(2) (i.e., clinically obese) but not on direct assay of a further 3,525 subjects. This mutation was predicted to be deleterious and analysis using a cyclic AMP (cAMP) responsive luciferase reporter assay showed substantial loss of function of the mutant receptor. This population-based mutation scan of MC4R suggests that there is no severe MC4R mutation with high prevalence in the United Kingdom, but that obesity-causing MC4R mutation at 1 in 1,100 might represent one of the commonest autosomal dominant disorders in man.

Aged↗
PubMed2007

The association of the paraoxonase (PON1) Q192R polymorphism with depression in older women: findings from the British Women's Heart and Health Study.

BACKGROUND: The association between the R allele of PON1 Q192R and symptoms reported by sheep dippers and Gulf War veterans has been used to suggest a biological basis for these symptoms. In the absence of such studies in non-occupational populations, these conclusions may not be valid. OBJECTIVE: To examine the association of paraoxonase (PON1) Q192R with a report of ever being diagnosed with depression among a random sample of 3266 British women, aged 60-79 years. RESULTS: The R allele of PON1 Q192R was associated with depression: per-allele odds ratio 1.22 (95% confidence interval: 1.05 to 1.41) in this population. CONCLUSIONS: These findings suggest that the association of PON1 Q192R with symptoms of depression in occupationally exposed groups may be driven by exposure to toxins that everyone in the general population is exposed to rather than exposure to toxins specifically used by sheep dippers or Gulf War veterans, or that other mechanisms underlie the association. This is because the study population in which we have found an association consisted of British women aged 60-79 years, few of whom were sheep dippers or Gulf War veterans. When using genotype-outcome associations to infer causality with respect to an environmental exposure modified by the genotype, it is important to examine these associations in general populations and in those specifically exposed to the putative agent. The possible role of PON1 Q192R in psychiatric morbidity requires further examination.

Aged↗
PubMed2006

Associations between tooth loss and mortality patterns in the Glasgow Alumni Cohort.

OBJECTIVE: To use data from the Glasgow Alumni Cohort to investigate whether oral health in young adulthood is independently associated with later life cardiovascular disease (CVD) and cancer mortality. METHODS AND RESULTS: Of the original cohort (n = 15 322), 12 631 subjects were traced through the National Health Service Central Register. Of these, 9569 men and 2654 women were 30 years or younger at baseline. During up to 57 years of follow-up, 1432 deaths occurred among subjects with complete data, including 509 deaths from CVD and 549 from cancer. After adjusting for potential confounders, no substantial association was found between the number of missing teeth (as a continuous variable) and all-cause mortality (hazard ratio (HR) for each extra missing tooth = 1.01; 95% confidence interval (CI) 1.00 to 1.02), CVD mortality (HR = 1.01; 95% CI 0.99 to 1.03) or cancer mortality (HR = 1.00; 95% CI 0.98 to 1.02). When the number of missing teeth was treated as a categorical variable, there was evidence that students with nine or more missing teeth at baseline had an increased risk of CVD (HR = 1.35; 95% CI 1.03 to 1.77) compared with those with fewer than five missing teeth. When the number of missing teeth was transformed using fractional polynomials, there seemed to be a non-linear relation between missing teeth and CVD mortality. CONCLUSIONS: Although some evidence was found to support the relation between tooth loss and CVD mortality, causal mechanisms underlying this association remain uncertain.

Adolescent↗
PubMed2006

Epidemiologic evidence for the fetal overnutrition hypothesis: findings from the mater-university study of pregnancy and its outcomes.

The fetal overnutrition hypothesis proposes that greater maternal adiposity results in increased obesity throughout life in the offspring. The authors examined the associations between parental prepregnancy body mass index (BMI; weight (kg)/height (m)(2)), based on height and weight reported by the mother at her first antenatal clinic visit, and offspring BMI (height and weight measured at age 14 years) in 3,340 parent-offspring trios from a birth cohort based in Brisbane, Australia (mothers were recruited in 1981-1984). The maternal-offspring BMI association was stronger than the paternal-offspring BMI association. In the fully adjusted model, the increase in standardized offspring BMI at age 14 for a one-standard-deviation (SD) increase in maternal BMI was 0.362 SD (95% confidence interval: 0.323, 0.402), and the corresponding result for a one-SD increase in paternal BMI was 0.239 SD (95% confidence interval: 0.197, 0.282). There was statistical support for a difference in the magnitude of the association between maternal-offspring BMI and paternal-offspring BMI in all confounder-adjusted models tested (all p's < 0.0001). In sensitivity analyses taking account of different plausible levels of nonpaternity (up to 15%), the greater maternal effect remained. These findings provide some support for the fetal overnutrition hypothesis.

Adolescent↗
PubMed2006

Social inequalities in antidepressant treatment and mortality: a longitudinal register study.

BACKGROUND: Despite an increased prevalence of depression among people of low socio-economic position, it remains unclear whether their treatment with antidepressants appropriately matches their increased need compared with people from more affluent backgrounds. This study examined socio-economic differences in antidepressant prescriptions and mortality related to depressive disorders. METHOD: A longitudinal register study of 17947 male and 47458 female local government employees with linked information on socio-economic indicators (education and occupational status) and data on antidepressant use and mortality associated with depressive disorder (suicide, alcohol-related deaths) during the years 1994 to 2000. RESULTS: In men, antidepressant treatment was less common among low educational groups than among high educational groups (OR 0.87, 95% CI 0.76-0.99) and a corresponding difference was seen between occupational statuses (OR for manual v. upper non-manual 0.72, 95% CI 0.62-0.84). In women, socio-economic position was not associated with antidepressant use. However, both among the men and women, employees with low socio-economic position had increased risk for mental-health-related mortality, as indicated by suicides, deaths from alcohol-related causes, and all-cause mortality. CONCLUSIONS: These data suggest a mismatch in the treatment of depression relative to apparent clinical need, with the lowest levels of treatment concentrated in the lower socio-economic groups, despite evidence of their increased prevalence of depression and suicide.

Adult↗
PubMed2006

Adult height and lung function as markers of life course exposures: associations with risk factors and cause-specific mortality.

BACKGROUND AND OBJECTIVE: Pulmonary function and height may be regarded as adult indices of exposures accumulated across the entire life course and in early life, respectively. As such, we hypothesised that pulmonary function would be more strongly related to mortality than height. Studies of the association of height and lung function with mortality--which are currently modest in number--will clarify the relative utility of these risk indices and the mechanisms underlying observed patterns of disease risk. DESIGN, SETTING, AND PARTICIPANTS: Data were drawn from the Whitehall study, a prospective cohort study of 18,403 middle-aged non-industrial London-based male government employees conducted in the late 1960s. Data were collected on stature, spirometry measures (including forced expiratory volume in one second [FEV1]) and a range of covariates. These analyses are based on the 3083 non-smoking men with complete data. MAIN OUTCOME MEASURES: Mortality ascribed to all-causes, cardiovascular disease, respiratory disease and site-specific cancers. RESULTS: Both height and FEV1 were associated with a range of physiological, behavioural and socio-economic risk factors. Relations with these risk factors were seen more frequently for FEV1 and, where they occurred, were of somewhat higher magnitude. During a maximum of 35 years follow-up, half the non-smokers had died (n = 1545). FEV1 (HR(per one SD increase); 0.89; 0.84, 0.95) was somewhat more strongly related to total mortality than height (0.96; 0.91, 1.01) in a fully adjusted model, but this difference did not attain statistical significance at conventional levels (p-value for difference = 0.15). Of the eight independent disease-specific outcomes examined, the only convincing evidence of a differential effect was for deaths from respiratory causes which was unsurprisingly more strongly related to FEV1 than height (p-value for difference = 0.03). CONCLUSIONS: In the present study, height and FEV1 were essentially similarly related to both risk factors and mortality outcomes, thus not providing support for our hypothesis. Both factors would appear to have some utility as markers of early life exposures.

Body Height↗
PubMed2006

Meta-analyses of observational and genetic association studies of folate intakes or levels and breast cancer risk.

BACKGROUND: Evidence from case-control studies suggests that increasing dietary folate intake is associated with a reduced risk of breast cancer. However, large cohort studies have found no such association, and animal studies suggest that folate supplementation may promote tumorigenesis. We conducted a meta-analysis to summarize the available evidence from observational studies on this issue and a meta-analysis of the association between a common polymorphism in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, a key enzyme in folate metabolism, and breast cancer risk. METHODS: We searched Medline and ISI Web of Knowledge databases for relevant studies that were published through May 31, 2006. We used random-effects analysis to calculate odds ratios (ORs) for case-control studies or relative risks (RRs) for cohort studies for a 100-microg/d increase in folate intake. Unadjusted odds ratios were calculated for the studies of MTHFR genotype based on published genotype frequencies. RESULTS: A total of 13 case-control studies and nine cohort studies were included in the meta-analysis of folate intake and breast cancer risk. We found a summary OR of 0.91 (95% confidence interval [CI] = 0.87 to 0.96) from the case-control studies and a summary RR of 0.99 (95% CI = 0.98 to 1.01) from the cohort studies for a 100-microg/d increase in folate intake. We found evidence that the case-control studies may have suffered from substantial publication bias. The case-control and cohort studies may have been subject to measurement error, confounding, and possibly spurious associations arising from subgroup analyses; in addition, the case-control studies were potentially subject to recall bias and publication bias. Seventeen studies were included in the meta-analysis of MTHFR C677T genotype and breast cancer risk. We found no difference in breast cancer risk between MTHFR 677 TT homozygotes and CC homozygotes (OR = 1.05, 95% CI = 0.88 to 1.25), and there was no evidence of an interaction between folate intake and MTHFR genotype on breast cancer risk. CONCLUSION: A lack of dietary folate intake is not associated with the risk of breast cancer.

5,10-Methylenetetrahydrofolate Reductase (FADH2)↗
PubMed2006

A common haplotype of the glucokinase gene alters fasting glucose and birth weight: association in six studies and population-genetics analyses.

Fasting glucose is associated with future risk of type 2 diabetes and ischemic heart disease and is tightly regulated despite considerable variation in quantity, type, and timing of food intake. In pregnancy, maternal fasting glucose concentration is an important determinant of offspring birth weight. The key determinant of fasting glucose is the enzyme glucokinase (GCK). Rare mutations of GCK cause fasting hyperglycemia and alter birth weight. The extent to which common variation of GCK explains normal variation of fasting glucose and birth weight is not known. We aimed to comprehensively define the role of variation of GCK in determination of fasting glucose and birth weight, using a tagging SNP (tSNP) approach and studying 19,806 subjects from six population-based studies. Using 22 tSNPs, we showed that the variant rs1799884 is associated with fasting glucose at all ages in the normal population and exceeded genomewide levels of significance (P=10-9). rs3757840 was also highly significantly associated with fasting glucose (P=8x10-7), but haplotype analysis revealed that this is explained by linkage disequilibrium (r2=0.2) with rs1799884. A maternal A allele at rs1799884 was associated with a 32-g (95% confidence interval 11-53 g) increase in offspring birth weight (P=.002). Genetic variation influencing birth weight may have conferred a selective advantage in human populations. We performed extensive population-genetics analyses to look for evidence of recent positive natural selection on patterns of GCK variation. However, we found no strong signature of positive selection. In conclusion, a comprehensive analysis of common variation of the glucokinase gene shows that this is the first gene to be reproducibly associated with fasting glucose and fetal growth.

Adult↗
PubMed2006

Association of childhood socioeconomic position with cause-specific mortality in a prospective record linkage study of 1,839,384 individuals.

Previous studies have lacked sufficient power to assess associations between early-life socioeconomic position and adult cause-specific mortality. The authors examined associations of parental social class at age 0-16 years with mortality among 1,824,064 Swedes born in 1944-1960. Females and males from manual compared with nonmanual childhood social classes were more likely to die from smoking-related cancers, stomach cancer, respiratory disease, cardiovascular disease, and diabetes. Males from manual compared with nonmanual social classes were more likely to die from unintentional injury, homicide, and alcoholic cirrhosis. The association with stomach cancer was little affected by adjustment for parental later-life and own adult social class or education. For other outcomes, educational attainment resulted in greater attenuation of associations than did adjustment for adult social class. Early-life social class was not related to suicide or to melanoma, colon, breast, brain, or lymphatic cancers or to leukemia. With the exception of stomach cancer, caused by Helicobacter pylori infection acquired in childhood, poorer social class in early life was associated with diseases largely caused by behavioral risk factors such as smoking, physical inactivity, and an unhealthy diet. Educational attainment may be important in reducing the health inequalities associated with early-life disadvantage.

Cause of Death↗
PubMed2006

Schizophrenia and neural tube defects: comparisons from an epidemiological perspective.

In this review, we examine and compare epidemiological studies of schizophrenia and neural tube defects (NTDs). Although there is no apparent link between these 2 disparate disorders in terms of clinical manifestation or phenotypes, overlapping patterns in the variation of incidence of schizophrenia with that of NTDs indicate the existence of one or more shared etiological risk factors. Evidence in support of such a phenomenon may enhance our understanding of underlying pathological mechanisms and may guide future studies of etiology and prevention. The similarities that occur in a number of epidemiological observations for these disorders are in keeping with a hypothesis of nutritional deficiencies in utero acting as a risk factor for both schizophrenia and NTDs. Programes of periconceptual folate and multivitamin supplementation aimed to reduce the risk of NTDs are already in place in many countries. Nevertheless, evidence of additional effects of specific maternal micronutrient deficiency on risk of schizophrenia may not only increase enthusiasm for expansion of such programes but also enhance understanding of etiology of this disorder and offer the potential for targeted interventions in high-risk groups.

Birth Intervals↗
PubMed2006

The publication process itself was the major cause of publication bias in genetic epidemiology.

OBJECTIVES: How do scientists in the field of genetic epidemiology see the problem of publication bias, what are the possible solutions and what particular pressures are they under that might either promote or prevent publication and other biases? STUDY DESIGN AND SETTING: An exploratory study of beliefs and practices among scientists working in the field of genetic epidemiology. A purposive sample of senior, genetic scientists was selected (N=6) and informants were interviewed face to face. RESULTS: There was some consensus that the issue of nonreplication might be particularly problematic in genetic epidemiology, and that publication bias could contribute to this. The informants suggested that the problem lay mainly with the publication process. Publication of negative results was seen as important but fraught with difficulties. CONCLUSION: Possible solutions included education of editors, and reviewers, dissemination of negative findings through Web sites or accessible data archives and pooling of data. However, none of these were perceived to be straightforward given the current pressures on the research industry.

Culture↗