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1.
Eur Heart J ; 2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33532862

RESUMO

AIMS: While most patients with myocardial infarction (MI) have underlying coronary atherosclerosis, not all patients with coronary artery disease (CAD) develop MI. We sought to address the hypothesis that some of the genetic factors which establish atherosclerosis may be distinct from those that predispose to vulnerable plaques and thrombus formation. METHODS AND RESULTS: We carried out a genome-wide association study for MI in the UK Biobank (n∼472 000), followed by a meta-analysis with summary statistics from the CARDIoGRAMplusC4D Consortium (n∼167 000). Multiple independent replication analyses and functional approaches were used to prioritize loci and evaluate positional candidate genes. Eight novel regions were identified for MI at the genome wide significance level, of which effect sizes at six loci were more robust for MI than for CAD without the presence of MI. Confirmatory evidence for association of a locus on chromosome 1p21.3 harbouring choline-like transporter 3 (SLC44A3) with MI in the context of CAD, but not with coronary atherosclerosis itself, was obtained in Biobank Japan (n∼165 000) and 16 independent angiography-based cohorts (n∼27 000). Follow-up analyses did not reveal association of the SLC44A3 locus with CAD risk factors, biomarkers of coagulation, other thrombotic diseases, or plasma levels of a broad array of metabolites, including choline, trimethylamine N-oxide, and betaine. However, aortic expression of SLC44A3 was increased in carriers of the MI risk allele at chromosome 1p21.3, increased in ischaemic (vs. non-diseased) coronary arteries, up-regulated in human aortic endothelial cells treated with interleukin-1ß (vs. vehicle), and associated with smooth muscle cell migration in vitro. CONCLUSIONS: A large-scale analysis comprising ∼831 000 subjects revealed novel genetic determinants of MI and implicated SLC44A3 in the pathophysiology of vulnerable plaques.

2.
Sci Adv ; 7(6)2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33547071

RESUMO

To characterize the genetic basis of facial features in Latin Americans, we performed a genome-wide association study (GWAS) of more than 6000 individuals using 59 landmark-based measurements from two-dimensional profile photographs and ~9,000,000 genotyped or imputed single-nucleotide polymorphisms. We detected significant association of 32 traits with at least 1 (and up to 6) of 32 different genomic regions, more than doubling the number of robustly associated face morphology loci reported until now (from 11 to 23). These GWAS hits are strongly enriched in regulatory sequences active specifically during craniofacial development. The associated region in 1p12 includes a tract of archaic adaptive introgression, with a Denisovan haplotype common in Native Americans affecting particularly lip thickness. Among the nine previously unidentified face morphology loci we identified is the VPS13B gene region, and we show that variants in this region also affect midfacial morphology in mice.

3.
Circulation ; 142(6): 546-555, 2020 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-32654539

RESUMO

BACKGROUND: Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD), are lacking. Given that coagulation is involved in the thrombus formation stage on atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD. METHODS: We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox proportional hazards regression models were used to obtain age- and sex-adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality. RESULTS: The studies included 69 681 individuals of whom 3190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61 147 participants and 6849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03 [95% CI, 0.92-1.16]; I2=28%; P-heterogeneity=0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality were also close to identity. CONCLUSIONS: Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population.

4.
Genet Epidemiol ; 44(8): 924-933, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32710482

RESUMO

It has been hypothesised that nonsyndromic cleft lip/palate (nsCL/P) and cancer may share aetiological risk factors. Population studies have found inconsistent evidence for increased incidence of cancer in nsCL/P cases, but several genes (e.g., CDH1, AXIN2) have been implicated in the aetiologies of both phenotypes. We aimed to evaluate shared genetic aetiology between nsCL/P and oral cavity/oropharyngeal cancers (OC/OPC), which affect similar anatomical regions. Using a primary sample of 5,048 OC/OPC cases and 5,450 controls of European ancestry and a replication sample of 750 cases and 336,319 controls from UK Biobank, we estimate genetic overlap using nsCL/P polygenic risk scores (PRS) with Mendelian randomization analyses performed to evaluate potential causal mechanisms. In the primary sample, we found strong evidence for an association between a nsCL/P PRS and increased odds of OC/OPC (per standard deviation increase in score, odds ratio [OR]: 1.09; 95% confidence interval [CI]: 1.04, 1.13; p = .000053). Although confidence intervals overlapped with the primary estimate, we did not find confirmatory evidence of an association between the PRS and OC/OPC in UK Biobank (OR 1.02; 95% CI: 0.95, 1.10; p = .55). Mendelian randomization analyses provided evidence that major nsCL/P risk variants are unlikely to influence OC/OPC. Our findings suggest possible shared genetic influences on nsCL/P and OC/OPC.

5.
Int J Epidemiol ; 49(4): 1282-1293, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32373937

RESUMO

BACKGROUND: Previous studies have found that children born with a non-syndromic orofacial cleft have lower-than-average educational attainment. Differences could be due to a genetic predisposition to low intelligence and academic performance, factors arising due to the cleft phenotype (such as social stigmatization, impaired speech/language development) or confounding by the prenatal environment. A clearer understanding of this mechanism will inform interventions to improve educational attainment in individuals born with a cleft, which could substantially improve their quality of life. We assessed evidence for the hypothesis that common variant genetic liability to non-syndromic cleft lip with or without cleft palate (nsCL/P) influences educational attainment. METHODS: We performed a genome-wide association study (GWAS) meta-analysis of nsCL/P with 1692 nsCL/P cases and 4259 parental and unrelated controls. Using GWAS summary statistics, we performed Linkage Disequilibrium (LD)-score regression to estimate the genetic correlation between nsCL/P, educational attainment (GWAS n = 766 345) and intelligence (GWAS n = 257 828). We used two-sample Mendelian randomization to evaluate the causal effects of genetic liability to nsCL/P on educational attainment and intelligence. RESULTS: There was limited evidence for shared genetic aetiology or causal relationships between nsCL/P and educational attainment [genetic correlation (rg) -0.05, 95% confidence interval (CI) -0.12 to 0.01, P 0.13; MR estimate (ßMR) -0.002, 95% CI -0.009 to 0.006, P 0.679) or intelligence (rg -0.04, 95% CI -0.13 to 0.04, P 0.34; ßMR -0.009, 95% CI -0.02 to 0.002, P 0.11). CONCLUSIONS: Common variants are unlikely to predispose individuals born with nsCL/P to low educational attainment or intelligence. This is an important first step towards understanding the aetiology of low educational attainment in this group.

6.
Hum Mol Genet ; 29(8): 1388-1395, 2020 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-32219344

RESUMO

BACKGROUND: There is growing evidence that polygenic risk scores (PRSs) can identify individuals with elevated lifetime risk of coronary artery disease (CAD). Whether they can also be used to stratify the risk of subsequent events among those surviving a first CAD event remain uncertain, with possible biological differences between CAD onset and progression, and the potential for index event bias. METHODS: Using two baseline subsamples of UK Biobank: prevalent CAD cases (N = 10 287) and individuals without CAD (N = 393 108), we evaluated associations between a CAD PRS and incident cardiovascular and fatal outcomes. RESULTS: A 1 SD higher PRS was associated with an increased risk of incident myocardial infarction (MI) in participants without CAD (OR 1.33; 95% CI 1.29, 1.38), but the effect estimate was markedly attenuated in those with prevalent CAD (OR 1.15; 95% CI 1.06, 1.25) and heterogeneity P = 0.0012. Additionally, among prevalent CAD cases, we found an evidence of an inverse association between the CAD PRS and risk of all-cause death (OR 0.91; 95% CI 0.85, 0.98) compared with those without CAD (OR 1.01; 95% CI 0.99, 1.03) and heterogeneity P = 0.0041. A similar inverse association was found for ischaemic stroke [prevalent CAD (OR 0.78; 95% CI 0.67, 0.90); without CAD (OR 1.09; 95% CI 1.04, 1.15), heterogeneity P < 0.001]. CONCLUSIONS: Bias induced by case stratification and survival into UK Biobank may distort the associations of PRS derived from case-control studies or populations initially free of disease. Differentiating between effects of possible biases and genuine biological heterogeneity is a major challenge in disease progression research.

7.
Elife ; 82019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31763980

RESUMO

The human face represents a combined set of highly heritable phenotypes, but knowledge on its genetic architecture remains limited, despite the relevance for various fields. A series of genome-wide association studies on 78 facial shape phenotypes quantified from 3-dimensional facial images of 10,115 Europeans identified 24 genetic loci reaching study-wide suggestive association (p < 5 × 10-8), among which 17 were previously unreported. A follow-up multi-ethnic study in additional 7917 individuals confirmed 10 loci including six unreported ones (padjusted < 2.1 × 10-3). A global map of derived polygenic face scores assembled facial features in major continental groups consistent with anthropological knowledge. Analyses of epigenomic datasets from cranial neural crest cells revealed abundant cis-regulatory activities at the face-associated genetic loci. Luciferase reporter assays in neural crest progenitor cells highlighted enhancer activities of several face-associated DNA variants. These results substantially advance our understanding of the genetic basis underlying human facial variation and provide candidates for future in-vivo functional studies.


Assuntos
Face/anatomia & histologia , Loci Gênicos/genética , Desenvolvimento Maxilofacial/genética , Fenótipo , Adolescente , Adulto , Pontos de Referência Anatômicos , Padronização Corporal/genética , Criança , Pré-Escolar , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Ontologia Genética , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Imageamento Tridimensional , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Adulto Jovem
8.
Nat Commun ; 10(1): 5039, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31745073

RESUMO

Alcohol use is correlated within spouse-pairs, but it is difficult to disentangle effects of alcohol consumption on mate-selection from social factors or the shared spousal environment. We hypothesised that genetic variants related to alcohol consumption may, via their effect on alcohol behaviour, influence mate selection. Here, we find strong evidence that an individual's self-reported alcohol consumption and their genotype at rs1229984, a missense variant in ADH1B, are associated with their partner's self-reported alcohol use. Applying Mendelian randomization, we estimate that a unit increase in an individual's weekly alcohol consumption increases partner's alcohol consumption by 0.26 units (95% C.I. 0.15, 0.38; P = 8.20 × 10-6). Furthermore, we find evidence of spousal genotypic concordance for rs1229984, suggesting that spousal concordance for alcohol consumption existed prior to cohabitation. Although the SNP is strongly associated with ancestry, our results suggest some concordance independent of population stratification. Our findings suggest that alcohol behaviour directly influences mate selection.


Assuntos
Álcool Desidrogenase/genética , Consumo de Bebidas Alcoólicas/genética , Alcoolismo/genética , Bancos de Espécimes Biológicos/estatística & dados numéricos , Casamento , Polimorfismo de Nucleotídeo Único , Adulto , Feminino , Genótipo , Humanos , Masculino , Fenótipo , Reprodução/genética , Autorrelato , Reino Unido
9.
Hum Mol Genet ; 28(R2): R170-R179, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31647093

RESUMO

Mendelian randomization (MR) is increasingly used to make causal inferences in a wide range of fields, from drug development to etiologic studies. Causal inference in MR is possible because of the process of genetic inheritance from parents to offspring. Specifically, at gamete formation and conception, meiosis ensures random allocation to the offspring of one allele from each parent at each locus, and these are unrelated to most of the other inherited genetic variants. To date, most MR studies have used data from unrelated individuals. These studies assume that genotypes are independent of the environment across a sample of unrelated individuals, conditional on covariates. Here we describe potential sources of bias, such as transmission ratio distortion, selection bias, population stratification, dynastic effects and assortative mating that can induce spurious or biased SNP-phenotype associations. We explain how studies of related individuals such as sibling pairs or parent-offspring trios can be used to overcome some of these sources of bias, to provide potentially more reliable evidence regarding causal processes. The increasing availability of data from related individuals in large cohort studies presents an opportunity to both overcome some of these biases and also to evaluate familial environmental effects.


Assuntos
Análise da Randomização Mendeliana , População/genética , Reprodução/genética , Família , Características da Família , Estudos de Associação Genética , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Viés de Seleção , Sociobiologia/educação
10.
J Am Med Inform Assoc ; 26(12): 1545-1559, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31329239

RESUMO

OBJECTIVE: Electronic health records (EHRs) are a rich source of information on human diseases, but the information is variably structured, fragmented, curated using different coding systems, and collected for purposes other than medical research. We describe an approach for developing, validating, and sharing reproducible phenotypes from national structured EHR in the United Kingdom with applications for translational research. MATERIALS AND METHODS: We implemented a rule-based phenotyping framework, with up to 6 approaches of validation. We applied our framework to a sample of 15 million individuals in a national EHR data source (population-based primary care, all ages) linked to hospitalization and death records in England. Data comprised continuous measurements (for example, blood pressure; medication information; coded diagnoses, symptoms, procedures, and referrals), recorded using 5 controlled clinical terminologies: (1) read (primary care, subset of SNOMED-CT [Systematized Nomenclature of Medicine Clinical Terms]), (2) International Classification of Diseases-Ninth Revision and Tenth Revision (secondary care diagnoses and cause of mortality), (3) Office of Population Censuses and Surveys Classification of Surgical Operations and Procedures, Fourth Revision (hospital surgical procedures), and (4) DM+D prescription codes. RESULTS: Using the CALIBER phenotyping framework, we created algorithms for 51 diseases, syndromes, biomarkers, and lifestyle risk factors and provide up to 6 validation approaches. The EHR phenotypes are curated in the open-access CALIBER Portal (https://www.caliberresearch.org/portal) and have been used by 40 national and international research groups in 60 peer-reviewed publications. CONCLUSIONS: We describe a UK EHR phenomics approach within the CALIBER EHR data platform with initial evidence of validity and use, as an important step toward international use of UK EHR data for health research.

11.
Circ Genom Precis Med ; 12(4): e002470, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30896328

RESUMO

BACKGROUND: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD. METHODS: The consortium currently includes 57 studies from 18 countries, recruiting 185 614 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events. RESULTS: Enrollment into the individual studies took place between 1985 to present day with a duration of follow-up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (hazard ratio, 1.15; 95% CI, 1.14-1.16) per 5-year increase, male sex (hazard ratio, 1.17; 95% CI, 1.13-1.21) and smoking (hazard ratio, 1.43; 95% CI, 1.35-1.51) with risk of subsequent CHD death or myocardial infarction and differing associations with other individual and composite cardiovascular endpoints. CONCLUSIONS: GENIUS-CHD is a global collaboration seeking to elucidate genetic and nongenetic determinants of subsequent event risk in individuals with established CHD, to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.


Assuntos
Doença das Coronárias/patologia , Adulto , Fatores Etários , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Risco , Fatores Sexuais , Fumar
12.
Circ Genom Precis Med ; 12(4): e002471, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30897348

RESUMO

BACKGROUND: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk. METHODS: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD. RESULTS: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUS-CHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction <0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09). CONCLUSIONS: In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.


Assuntos
Cromossomos Humanos Par 9 , Doença da Artéria Coronariana/patologia , Estudos de Casos e Controles , Doença da Artéria Coronariana/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Razão de Chances , Fatores de Risco
13.
Drug Alcohol Depend ; 197: 42-47, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30772781

RESUMO

BACKGROUND: High levels of prenatal alcohol exposure are known to cause an array of adverse outcomes including fetal alcohol syndrome (FAS); however, the effects of low to moderate exposure are less-well characterized. Previous findings suggest that differences in normal-range facial morphology may be a marker for alcohol exposure and related adverse effects. METHODS: 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. RESULTS: In both self-reported alcohol consumption (N = 4233) and rs1229984 genotype (N = 3139) 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 centered around zero. CONCLUSIONS: There is no strong evidence, in a sample representative of the general population, for an effect of prenatal alcohol exposure on normal-range variation in facial morphology.


Assuntos
Face/anormalidades , Transtornos do Espectro Alcoólico Fetal/etiologia , Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Adulto , Álcool Desidrogenase/análise , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/genética , Biomarcadores/análise , Criança , Face/patologia , Feminino , Transtornos do Espectro Alcoólico Fetal/patologia , Genótipo , Humanos , Estudos Longitudinais , Masculino , Fenótipo , Gravidez , Complicações na Gravidez/genética , Complicações na Gravidez/psicologia , Reino Unido
14.
Epigenomics ; 11(2): 133-145, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30638414

RESUMO

AIM: To determine if nonsyndromic cleft lip with or without cleft palate (nsCL/P) genetic risk variants influence liability to nsCL/P through gene regulation pathways, such as those involving DNA methylation. MATERIALS & METHODS: nsCL/P genetic summary data and methylation data from four studies were used in conjunction with Mendelian randomization and joint likelihood mapping to investigate potential mediation of nsCL/P genetic variants. RESULTS & CONCLUSION: Evidence was found at 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, suggesting that genetic variation at these loci may increase liability to nsCL/P by influencing DNA methylation. Follow-up analyses using different tissues and gene expression data provided further insight into possible biological mechanisms.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Metilação de DNA , Variação Genética , Criança , Fenda Labial/patologia , Fissura Palatina/patologia , Epigênese Genética , Feminino , Proteínas de Homeodomínio/genética , Humanos , Masculino , Análise da Randomização Mendeliana , Netrina-1/genética , Fatores de Transcrição/genética
15.
Front Genet ; 9: 462, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30386375

RESUMO

Historically, craniofacial genetic research has understandably focused on identifying the causes of craniofacial anomalies and it has only been within the last 10 years, that there has been a drive to detail the biological basis of normal-range facial variation. This initiative has been facilitated by the availability of low-cost hi-resolution three-dimensional systems which have the ability to capture the facial details of thousands of individuals quickly and accurately. Simultaneous advances in genotyping technology have enabled the exploration of genetic influences on facial phenotypes, both in the present day and across human history. There are several important reasons for exploring the genetics of normal-range variation in facial morphology.     - Disentangling the environmental factors and relative parental biological contributions to heritable traits can help to answer the age-old question "why we look the way that we do?"     - Understanding the etiology of craniofacial anomalies; e.g., unaffected family members of individuals with non-syndromic cleft lip/palate (nsCL/P) have been shown to differ in terms of normal-range facial variation to the general population suggesting an etiological link between facial morphology and nsCL/P.     - Many factors such as ancestry, sex, eye/hair color as well as distinctive facial features (such as, shape of the chin, cheeks, eyes, forehead, lips, and nose) can be identified or estimated using an individual's genetic data, with potential applications in healthcare and forensics.     - Improved understanding of historical selection and adaptation relating to facial phenotypes, for example, skin pigmentation and geographical latitude.     - Highlighting what is known about shared facial traits, medical conditions and genes.

16.
PLoS Genet ; 14(8): e1007501, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30067744

RESUMO

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 = 2x10-5). 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.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Lábio/anormalidades , Adolescente , Adulto , Criança , Pré-Escolar , Grupos de Populações Continentais/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Técnicas de Genotipagem , Humanos , Estudos Longitudinais , Herança Multifatorial , Fenótipo , Polimorfismo de Nucleotídeo Único , Adulto Jovem
17.
Sci Rep ; 7(1): 11655, 2017 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-28912458

RESUMO

Many psychiatric traits are sexually dimorphic in terms of prevalence, age of onset, progression and prognosis; sex chromosomes could play a role in these differences. In this study we evaluated the association between Y chromosome and mitochondrial DNA haplogroups with sexually-dimorphic behavioural and psychiatric traits. The study sample included 4,211 males and 4,009 females with mitochondrial DNA haplogroups and 4,788 males with Y chromosome haplogroups who are part of the Avon Longitudinal Study of Parents and Children (ALSPAC) based in the United Kingdom. Different subsets of these populations were assessed using measures of behavioural and psychiatric traits with logistic regression being used to measure the association between haplogroups and the traits. The majority of behavioural traits in our cohort differed between males and females; however Y chromosome and mitochondrial DNA haplogroups were not associated with any of the variables. These findings suggest that if there is common variation on the Y chromosome and mitochondrial DNA associated with behavioural and psychiatric trait variation, it has a small effect.


Assuntos
Comportamento Infantil , Cromossomos Humanos Y , DNA Mitocondrial , Característica Quantitativa Herdável , Criança , Cognição , Feminino , Estudos de Associação Genética , Haplótipos , Humanos , Masculino , Razão de Chances , Fenótipo , Polimorfismo de Nucleotídeo Único
18.
Drug Alcohol Depend ; 178: 143-149, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28647682

RESUMO

BACKGROUND: Smoking influences body weight, but there is little evidence as to whether body mass index (BMI) and body dissatisfaction increase smoking initiation in adolescents. METHODS: We evaluated the association between measured BMI, body dissatisfaction and latent classes of smoking initiation (never smokers, experimenters, late onset regular smokers, early onset regular smokers) in the Avon Longitudinal Study of Parents and Children. In observational analyses we used BMI (N=3754) and body dissatisfaction at age 10.5 years (N=3349). In Mendelian randomisation (MR) analysis, we used a BMI genetic risk score of 76 single nucleotide polymorphisms (N=4017). RESULTS: In females, higher BMI was associated with increased odds of early onset regular smoking (OR: 1.11, 95% CI: 1.04, 1.18) compared to being a never smoker, but not clearly associated with experimenting with smoking (OR: 1.04, 95% CI: 0.99, 1.10) or late onset regular smoking (OR: 1.01, 95% CI: 0.94, 1.09). No clear evidence was found for associations between BMI and smoking initiation classes in males (p-value for sex interaction≤0.001). Body dissatisfaction was associated with increased odds of late-onset regular smoking (OR: 1.71, 95% CI: 1.32, 1.99) in males and females combined (P-value for sex interaction=0.32). There was no clear evidence for an association between the BMI genetic risk score and smoking latent classes in males or females but estimates were imprecise. CONCLUSIONS: BMI in females and body dissatisfaction in males and females are associated with increased odds of smoking initiation, highlighting these as potentially important factors for consideration in smoking prevention strategies.


Assuntos
Comportamento do Adolescente/psicologia , Imagem Corporal/psicologia , Índice de Massa Corporal , Fumar Tabaco/tendências , Adolescente , Peso Corporal/fisiologia , Criança , Feminino , Humanos , Estudos Longitudinais , Masculino , Pais/psicologia , Fatores de Risco
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