Biology subjects

Lewis, S. J.

Publications and source records attributed to Lewis, S. J..

11 recordsLinked to original sources

bioRxiv2018

Cleft lip/palate and educational attainment: cause, consequence, or correlation? A Mendelian randomization study

ImportancePrevious studies have found that children born with a non-syndromic form of cleft lip and/or palate have lower-than-average educational attainment. These differences could be due to a genetic predisposition to low intelligence and academic performance, factors arising due to the cleft phenotype (such as school absence, social stigmatization and impaired speech and language development), or confounding by the prenatal environment. A clearer understanding of this mechanism will inform development of interventions to improve educational attainment in individuals born with a cleft, which could have wide-ranging knock-on effects on their quality of life.\n\nObjectiveTo assess evidence for the hypothesis that common variant genetic liability to non-syndromic cleft lip with or without cleft palate (nsCL/P) influences educational attainment.\n\nDesignUsing summary data from genome-wide association studies (GWAS), we performed Linkage Disequilibrium (LD)-score regression and two-sample Mendelian randomization to evaluate the relationship between genetic liability to nsCL/P (GWAS n=3,987) and educational attainment (GWAS n=766,345), and intelligence (GWAS n=257,828).\n\nResultsThere was little evidence for shared genetic aetiology between nsCL/P and educational attainment (rg -0.03, 95% CI -0.14 to 0.08, P 0.58; {beta}MR 0.002, 95% CI -0.001 to 0.005, P 0.417) or intelligence (rg -0.01, 95% CI -0.12 to 0.10, P 0.85; {beta}MR 0.002, 95% CI -0.010 to 0.014, P 0.669).\n\nConclusions and relevanceCommon genetic variants are unlikely to predispose individuals born with nsCL/P to low educational attainment or intelligence. This information will help tailor clinical-, school-, social- and family-level interventions to improve educational attainment in this group.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSDo children born with a non-syndromic cleft lip with or without palate (nsCL/P) have lower-than average academic achievement because of an underlying genetic predisposition to educational attainment and/or intelligence?\n\nFindingsThere was little evidence for shared common variant genetic correlation between nsCL/P, educational attainment and intelligence.\n\nMeaningCommon genetic variants are unlikely to predispose individuals born with nsCL/P to low educational attainment or intelligence. This information will help tailor clinical-, school-, social- and family-level interventions to improve educational attainment in this group.

genetics↗

bioRxiv2018

Alcohol consumption and mate choice in UK Biobank: comparing observational and Mendelian randomization estimates

Alcohol use is correlated within spouse-pairs, but it is difficult to disentangle the effects of alcohol consumption on mate-selection from social factors or cohabitation leading to spouses becoming more similar over time. We hypothesised that genetic variants related to alcohol consumption may, via their effect on alcohol behaviour, influence mate selection. Therefore, in a sample of over 47,000 spouse-pairs in the UK Biobank we utilised a well-characterised alcohol related variant, rs1229984 in ADH1B, as a genetic proxy for alcohol use. We compared the phenotypic concordance between spouses for self-reported alcohol use with the association between an individuals self-reported alcohol use and their partners rs1229984 genotype using Mendelian randomization. This was followed up by an exploration of the spousal genotypic concordance for the variant and an analysis determining if relationship length may be related to spousal alcohol behaviour similarities. We found strong evidence that both an individuals self-reported alcohol consumption and rs1229984 genotype are associated with their partners self-reported alcohol use. The Mendelian randomization analysis found that each unit increase in an individuals weekly alcohol consumption increased their partners alcohol consumption by 0.26 units (95% C.I. 0.15, 0.38; P=1.10x10-5). Furthermore, the rs1229984 genotype was concordant within spouse-pairs, suggesting that some spousal concordance for alcohol consumption existed prior to cohabitation. Although the SNP is strongly associated with ancestry, our results suggest that this concordance is unlikely to be explained by population stratification. Overall, our findings suggest that alcohol behaviour directly influences mate selection.

genetics↗

bioRxiv2018

Changes in structural network topology correlate with severity of hallucinatory behaviour in Parkinson’s disease

An inefficient integration between bottom-up visual input and higher-order visual processing regions is implicated in the manifestation of visual hallucinations (VH) in Parkinsons disease (PD). Using graph theory, the current study aimed to investigate white matter contributions to this perceptual imbalance hypothesis. Twenty-nine PD patients reported their hallucinatory behaviour on a questionnaire and performed a behavioural test that has been shown to elicit misperceptions. A composite score derived from these measures was used as a proxy for hallucinations severity and was correlated to connectivity strength of the network using the Network Based Statistic approach. The results showed that the severity of VH was associated with reduced connectivity within a large sub-network. This network included the majority of the diverse club and showed overall greater between- and within-module scores, compared to nodes not associated with hallucination severity. Furthermore, a reduction in between-module connectivity in the lateral occipital cortex, insula and pars orbitalis, as well as decreased within-module connectivity in the prefrontal, somatosensory and primary visual cortices were associated with VH severity. In contrast, the severity of VH was associated with an increase in between- and within-module connectivity in the orbitofrontal and temporal cortex, as well as regions comprising the dorsal attentional and DMN. These results suggest that the severity of VHs is associated with marked alterations in structural network topology, highlighted by a reduction in connectivity strength across a large sub-network, as well as changes in participation across top-down visual processing centres, visual and attentional networks. Therefore, impaired integration across the perceptual hierarchy may result in the inefficient transfer of information that gives rise to VHs in PD.

neuroscience↗

bioRxiv2018

Dopamine Depletion Alters Macroscopic Network Dynamics in Parkinsons Disease

AbstractParkinsons disease is primarily characterised by diminished dopaminergic function, however the impact of these impairments on large-scale brain dynamics remains unclear. It has been difficult to disentangle the direct effects of Parkinsons disease from compensatory changes that reconfigure the functional signature of the whole brain network. To examine the causal role of dopamine depletion in network-level topology, we investigated time-varying network structure in 37 individuals with idiopathic Parkinsons disease, both On and Off dopamine replacement therapy, along with 50 age-matched, healthy control subjects using resting-state functional MRI. By tracking dynamic network-level topology, we found that the Parkinsons disease Off state was associated with greater network-level integration than in the On state. The extent of integration in the Off state inversely correlated with motor symptom severity, suggesting that a shift toward a more integrated network topology may be a compensatory mechanism associated with preserved motor function in the dopamine depleted Off state. Furthermore, we were able to demonstrate that measures of both cognitive and brain reserve (i.e., premorbid intelligence and whole brain grey matter volume) had a positive relationship with the relative increase in network integration observed in the dopaminergic Off state. This suggests that each of these factors plays an important role in promoting network integration in the dopaminergic Off state. Our findings provide a mechanistic basis for understanding the PD Off state and provide a further conceptual link with network-level reconfiguration. Together, our results highlight the mechanisms responsible for pathological and compensatory change in Parkinsons disease.

neuroscience↗

bioRxiv2018

Prenatal alcohol exposure and facial morphology in a UK cohort

High levels of prenatal alcohol exposure are known to cause an array of adverse outcomes including foetal alcohol syndrome (FAS); however, the effects of low to moderate exposure are less-well characterised. Previous findings suggest that differences in normal-range facial morphology may be a marker for alcohol exposure and related adverse effects. Therefore, in the Avon Longitudinal Study of Parents and Children, we tested for an association between maternal alcohol consumption and six FAS-related facial phenotypes in their offspring, using both self-report questionnaires and the maternal genotype at rs1229984 in ADH1B as measures of maternal alcohol consumption. In both self-reported alcohol consumption (N=4,233) and rs1229984 genotype (N=3,139) analyses, we found no strong statistical evidence for an association between maternal alcohol consumption and facial phenotypes tested. The directions of effect estimates were compatible with the known effects of heavy alcohol exposure, but confidence intervals were largely centred around zero. We conclude that, in a sample representative of the general population, there is no strong evidence for an effect of prenatal alcohol exposure on normal-range variation in facial morphology.

epidemiology↗

bioRxiv2018

Mendelian randomization does not support serum calcium in prostate cancer risk

Background: Observational studies suggest that dietary and serum calcium are risk factors for prostate cancer. However, such studies suffer from residual confounding (due to unmeasured or imprecisely measured confounders), undermining causal inference. Mendelian randomization uses randomly assigned (hence unconfounded and pre-disease onset) germline genetic variation to proxy for phenotypes and strengthen causal inference in observational studies.\n\nObjective: We tested the hypothesis that serum calcium is associated with an increased risk of overall and advanced prostate cancer.\n\nDesign: A genetic instrument was constructed using 5 single nucleotide polymorphisms robustly associated with serum calcium in a genome-wide association study (N [≤] 61,079). This instrument was then used to test the effect of a 0.5 mg/dL increase (1 standard deviation, SD) in serum calcium on risk of prostate cancer in 72,729 men in the PRACTICAL (Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome) Consortium (44,825 cases, 27,904 controls) and risk of advanced prostate cancer in 33,498 men (6,263 cases, 27,235 controls).\n\nResults: We found weak evidence for a protective effect of serum calcium on prostate cancer risk (odds ratio [OR] per 0.5 mg/dL increase in calcium: 0.83, 95% CI: 0.63-1.08; P=0.12). We did not find strong evidence for an effect of serum calcium on advanced prostate cancer (OR per 0.5 mg/dL increase in calcium: 0.98, 95% CI: 0.57-1.70; P=0.93).\n\nConclusions: Our Mendelian randomization analysis does not support the hypothesis that serum calcium increases risk of overall or advanced prostate cancer.

epidemiology↗

bioRxiv2018

DNA methylation mediates genetic liability to non-syndromic cleft lip/palate

BackgroundNon-syndromic cleft lip/palate (nsCL/P) is a complex trait with genetic and environmental risk factors. Around 40 distinct genetic risk loci have been identified for nsCL/P, but many reside in non-protein-coding regions with an unclear function. We hypothesised that one possibility is that the genetic risk variants influence susceptibility to nsCL/P through gene regulation pathways, such as those involving DNA methylation.\n\nMethodsUsing nsCL/P Genome-wide association study summary data and methylation data from four studies, we used Mendelian randomization and joint likelihood mapping to identify putative loci where genetic liability to nsCL/P may be mediated by variation in DNA methylation in blood.\n\nResultsThere was evidence at three independent loci, VAX1 (10q25.3), LOC146880 (17q23.3) and NTN1 (17p13.1), that liability to nsCL/P and variation in DNA methylation might be driven by the same genetic variant. Follow up analyses using DNA methylation data, derived from lip and palate tissue, and gene expression catalogues provided further insight into possible biological mechanisms.\n\nConclusionsGenetic variation may increase liability to nsCL/P by influencing DNA methylation and gene expression at VAX1, LOC146880 and NTN1.

genetics↗

bioRxiv2018

Investigating the shared genetics of non-syndromic cleft lip/palate and facial morphology

There is increasing evidence that genetic risk variants for non-syndromic cleft lip/palate (nsCL/P) are also associated with normal-range variation in facial morphology. However, previous analyses are mostly limited to candidate SNPs and findings have not been consistently replicated. Here, we used polygenic risk scores (PRS) to test for genetic overlap between nsCL/P and seven biologically relevant facial phenotypes. Where evidence was found of genetic overlap, we used bidirectional Mendelian randomization (MR) to test the hypothesis that genetic liability to nsCL/P is causally related to implicated facial phenotypes. Across 5,804 individuals of European ancestry from two studies, we found strong evidence, using PRS, of genetic overlap between nsCL/P and philtrum width; a 1 S.D. increase in nsCL/P PRS was associated with a 0.10 mm decrease in philtrum width (95% C.I. 0.054, 0.146; P = 0.00002). Follow-up MR analyses supported a causal relationship; genetic variants for nsCL/P homogeneously cause decreased philtrum width. In addition to the primary analysis, we also identified two novel risk loci for philtrum width at 5q22.2 and 7p15.2 in our Genome-wide Association Study (GWAS) of 6,136 individuals. Our results support a liability threshold model of inheritance for nsCL/P, related to abnormalities in development of the philtrum.

genetics↗

bioRxiv2017

Causal inference in cancer epidemiology: what is the role of Mendelian randomization?

Observational epidemiological studies are prone to confounding, measurement error, and reverse causation, undermining their ability to generate reliable causal estimates of the effect of risk factors to inform cancer prevention and treatment strategies. Mendelian randomization (MR) is an analytical approach that uses genetic variants to proxy potentially modifiable exposures (e.g. environmental factors, biological traits, and druggable pathways) to permit robust causal inference of the effects of these exposures on diseases and their outcomes. MR has seen widespread adoption within population health research in cardio-metabolic disease, but also holds much promise for identifying possible interventions (e.g., dietary, behavioural, or pharmacological) for cancer prevention and treatment. However, some methodological and conceptual challenges in the implementation of MR are particularly pertinent when applying this method to cancer aetiology and prognosis, including reverse causation arising from disease latency and selection bias in studies of cancer progression. These issues must be carefully considered to ensure appropriate design, analysis, and interpretation of such studies.\n\nIn this review, we provide an overview of the key principles and assumptions of MR focusing on applications of this method to the study of cancer aetiology and prognosis. We summarize recent studies in the cancer literature that have adopted a MR framework to highlight strengths of this approach compared to conventional epidemiological studies. Lastly, limitations of MR and recent methodological developments to address them are discussed, along with the translational opportunities they present to inform public health and clinical interventions in cancer.

epidemiology↗

bioRxiv2017

Circulating selenium and prostate cancer risk: a Mendelian randomization analysis

In the Selenium and Vitamin E Cancer Prevention Trial (SELECT), selenium supplementation (causing a median 114 g/L increase in circulating selenium) did not lower overall prostate cancer risk, but increased risk of high-grade prostate cancer and type 2 diabetes. Mendelian randomization analysis uses genetic variants to proxy modifiable risk factors and can strengthen causal inference in observational studies. We constructed a genetic risk score comprising eleven single-nucleotide polymorphisms robustly (P<5x10-8) associated with circulating selenium in genome-wide association studies. In a Mendelian randomization analysis of 72,729 men in the PRACTICAL Consortium (44,825 cases, 27,904 controls), 114 g/L higher genetically-elevated circulating selenium was not associated with prostate cancer (OR: 1.01; 95% CI: 0.89-1.13). Concordant with findings from SELECT, selenium was weakly associated with advanced (including high-grade) prostate cancer (OR: 1.21; 95% CI: 0.98-1.49) and type 2 diabetes (OR: 1.18; 95% CI: 0.97-1.43; in a type 2 diabetes GWAS meta-analysis with up to 49,266 cases, 249,906 controls). Mendelian randomization mirrored the outcome of selenium supplementation in SELECT and may offer an approach for the prioritization of interventions for follow-up in large-scale randomized controlled trials.

epidemiology↗

bioRxiv2017

Distinct Blood DNA Methylation Profiles In Subtypes Of Orofacial Cleft

BackgroundThere is evidence that different subtypes of orofacial cleft have distinct aetiologies, although the precise molecular mechanisms underlying these are unknown. Given the key role of epigenetic processes such as DNA methylation in embryonic development, it is likely that aberrant DNA methylation may also play a part in the development of orofacial clefts.\n\nMethodsIn this study, we explored whether blood samples from children with different cleft subtypes showed distinct DNA methylation profiles.\n\nIn whole blood samples from 150 children from the Cleft Collective cohort study, we measured DNA methylation at over 450,000 sites on the genome. We then carried out epigenome-wide association studies (EWAS) to test the association between methylation at each site and cleft subtype (cleft lip only CLO n=50; cleft palate only CPO n=50; cleft lip and palate CLP n=50).\n\nResultsWe found four genomic regions differentially methylated in CLO compared to CLP, 17 in CPO compared to CLP and 294 in CPO compared to CLO. These regions included several mapping to genes that have previously been implicated in the development of orofacial clefts (for example, TBX1, COL11A2, HOXA2, PDGFRA) and over 250 novel associations.\n\nConclusionOur finding of distinct methylation profiles in different cleft subtypes might reflect differences in their aetiologies, with DNA methylation either playing a causal role in development of OFC subtypes or reflecting causal genetic or environmental factors.

epidemiology↗