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2.
Wellcome Open Res ; 5: 210, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32995559

RESUMO

The Avon Longitudinal Study of Parents and Children (ALSPAC) is a prospective population-based cohort study which recruited pregnant women in 1990-1992 and has followed these women, their partners and their offspring ever since. The study reacted rapidly to the coronavirus disease 2019 (COVID-19) pandemic, deploying an online questionnaire early on during lockdown (from 9 th April to 15 th May). In late May 2020, a second questionnaire was developed asking about physical and mental health, lifestyle and behaviours, employment and finances. The online questionnaire was deployed across the parent and offspring generations between the 26th May and 5 th July 2020. 6482 participants completed the questionnaire (2639 original mothers, 1039 original fathers/partners, 2711 offspring (mean age ~28 years) and 93 partners of offspring). 1039 new participants who did not respond to the first questionnaire deployed in April completed the second questionnaire.  A positive COVID-19 was reported by 36 (0.6%) participants (12 G0 and 24 G1), 91 (1.4%; 35 G0 and 56 G1) reported that they had been told by a doctor they likely had COVID-19 and 838 (13%; 422 G0 and 416 G1) suspected that they have had COVID-19.  Using algorithmically estimated cases based on symptoms, we estimate that the predicted prevalence of COVID-19 from mid-April to time of questionnaire completion was 3.1%. Data from both COVID questionnaires will be complemented with linkage to health records and results of biological testing as they become available. Data has been released as an update to the original dataset released in May 2020. It comprises: 1) a standard dataset containing all participant responses to both questionnaires with key sociodemographic factors and 2) as a composite release coordinating data from the existing resource, thus enabling bespoke research across all areas supported by the study. This data note describes the second questionnaire and the data obtained from it.

3.
Eur J Hum Genet ; 2020 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-33011735

RESUMO

Hypothesis-free Mendelian randomization studies provide a way to assess the causal relevance of a trait across the human phenome but can be limited by statistical power, sample overlap or complicated by horizontal pleiotropy. The recently described latent causal variable (LCV) approach provides an alternative method for causal inference which might be useful in hypothesis-free experiments across human phenome. We developed an automated pipeline for phenome-wide tests using the LCV approach including steps to estimate partial genetic causality, filter to a meaningful set of estimates, apply correction for multiple testing and then present the findings in a graphical summary termed causal architecture plot. We apply this pipeline to body mass index (BMI) and lipid traits as exemplars of traits where there is strong prior expectation for causal effects, and to dental caries and periodontitis as exemplars of traits where there is a need for causal inference. The results for lipids and BMI suggest that these traits are best viewed as contributing factors on a multitude of traits and conditions, thus providing additional evidence that supports viewing these traits as targets for interventions to improve health. On the other hand, caries and periodontitis are best viewed as a downstream consequence of other traits and diseases rather than a cause of ill health. The automated pipeline is implemented in the Complex-Traits Genetics Virtual Lab ( https://vl.genoma.io ) and results are available in https://view.genoma.io . We propose causal architecture plots based on phenome-wide partial genetic causality estimates as a new way visualizing the overall causal map of the human phenome.

4.
Microorganisms ; 8(8)2020 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-32726935

RESUMO

Maintaining a symbiotic oral microbiota is essential for oral and dental health, and host genetic factors may affect the composition or function of the oral microbiota through a range of possible mechanisms, including immune pathways. The study included 836 Swedish twins divided into separate groups of adolescents (n = 418) and unrelated adults (n = 418). Oral microbiota composition and functions of non-enzymatically lysed oral bacteria samples were evaluated using 16S rRNA gene sequencing and functional bioinformatics tools in the adolescents. Adaptive immune responses were assessed by testing for serum IgG antibodies against a panel of common oral bacteria in adults. In the adolescents, host genetic factors were associated with both the detection and abundance of microbial species, but with considerable variation between species. Host genetic factors were associated with predicted microbiota functions, including several functions related to bacterial sucrose, fructose, and carbohydrate metabolism. In adults, genetic factors were associated with serum antibodies against oral bacteria. In conclusion, host genetic factors affect the composition of the oral microbiota at a species level, and host-governed adaptive immune responses, and also affect the concerted functions of the oral microbiota as a whole. This may help explain why some people are genetically predisposed to the major dental diseases of caries and periodontitis.

5.
J Invest Dermatol ; 140(12): 2380-2385, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32339537

RESUMO

Failure of dermal protection or repair mechanisms might lead to visibly aged skin. The study aimed to identify genetic associations with perceived age. A genome-wide association study was undertaken in 423,992 adult participants of UK Biobank, using questionnaire data on perceived age and genetic data imputed to the Haplotype Reference Consortium imputation panel. The study identified 74 independently associated genetic loci, to our knowledge previously unreported (P < 5 × 10-8), which were enriched for cell signaling pathways, including the NEK6 and SMAD2 subnetworks. Common genetic variation was estimated to account for 14% of variation in perceived age, and the heritability of perceived age was partially shared with that of 75 other traits, including multiple traits representing adiposity, suggesting that perceived age may be a useful proxy trait in genetic association studies.

6.
Nutrients ; 12(3)2020 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-32138214

RESUMO

Oral microbiota ecology is influenced by environmental and host conditions, but few studies have evaluated associations between untargeted measures of the entire oral microbiome and potentially relevant environmental and host factors. This study aimed to identify salivary microbiota cluster groups using hierarchical cluster analyses (Wards method) based on 16S rRNA gene amplicon sequencing, and identify lifestyle and host factors which were associated with these groups. Group members (n = 175) were distinctly separated by microbiota profiles and differed in reported sucrose intake and allelic variation in the taste-preference-associated genes TAS1R1 (rs731024) and GNAT3 (rs2074673). Groups with higher sucrose intake were either characterized by a wide panel of species or phylotypes with fewer aciduric species, or by a narrower profile that included documented aciduric- and caries-associated species. The inferred functional profiles of the latter type were dominated by metabolic pathways associated with the carbohydrate metabolism with enrichment of glycosidase functions. In conclusion, this study supported in vivo associations between sugar intake and oral microbiota ecology, but it also found evidence for a variable microbiota response to sugar, highlighting the importance of modifying host factors and microbes beyond the commonly targeted acidogenic and acid-tolerant species. The results should be confirmed under controlled settings with comprehensive phenotypic and genotypic data.

7.
Am J Hum Genet ; 106(3): 327-337, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32059762

RESUMO

We aimed to increase our understanding of the genetic determinants of vitamin D levels by undertaking a large-scale genome-wide association study (GWAS) of serum 25 hydroxyvitamin D (25OHD). To do so, we used imputed genotypes from 401,460 white British UK Biobank participants with available 25OHD levels, retaining single-nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) > 0.1% and imputation quality score > 0.3. We performed a linear mixed model GWAS on standardized log-transformed 25OHD, adjusting for age, sex, season of measurement, and vitamin D supplementation. These results were combined with those from a previous GWAS including 42,274 Europeans. In silico functional follow-up of the GWAS results was undertaken to identify enrichment in gene sets, pathways, and expression in tissues, and to investigate the partitioned heritability of 25OHD and its shared heritability with other traits. Using this approach, the SNP heritability of 25OHD was estimated to 16.1%. 138 conditionally independent SNPs were detected (p value < 6.6 × 10-9) among which 53 had MAF < 5%. Single variant association signals mapped to 69 distinct loci, among which 63 were previously unreported. We identified enrichment in hepatic and lipid metabolism gene pathways and enriched expression of the 25OHD genes in liver, skin, and gastrointestinal tissues. We observed partially shared heritability between 25OHD and socio-economic traits, a feature which may be mediated through time spent outdoors. Therefore, through a large 25OHD GWAS, we identified 63 loci that underline the contribution of genes outside the vitamin D canonical metabolic pathway to the genetic architecture of 25OHD.


Assuntos
Estudo de Associação Genômica Ampla , Vitamina D/análogos & derivados , Feminino , Interação Gene-Ambiente , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Vitamina D/sangue
8.
Hum Genet ; 139(1): 43-44, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31363835

RESUMO

In the original article publication, there is an incorrect impression that Fig. 1 formed a formal Directed Acyclic Graph (DAG) by describing it as a causal model. However, it was not correct if interpreted in this way.

9.
Hum Genet ; 139(1): 23-41, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31030318

RESUMO

Replicable genetic association signals have consistently been found through genome-wide association studies in recent years. The recent dramatic expansion of study sizes improves power of estimation of effect sizes, genomic prediction, causal inference, and polygenic selection, but it simultaneously increases susceptibility of these methods to bias due to subtle population structure. Standard methods using genetic principal components to correct for structure might not always be appropriate and we use a simulation study to illustrate when correction might be ineffective for avoiding biases. New methods such as trans-ethnic modeling and chromosome painting allow for a richer understanding of the relationship between traits and population structure. We illustrate the arguments using real examples (stroke and educational attainment) and provide a more nuanced understanding of population structure, which is set to be revisited as a critical aspect of future analyses in genetic epidemiology. We also make simple recommendations for how problems can be avoided in the future. Our results have particular importance for the implementation of GWAS meta-analysis, for prediction of traits, and for causal inference.


Assuntos
Algoritmos , Bancos de Espécimes Biológicos/estatística & dados numéricos , Genética Populacional , Estudo de Associação Genômica Ampla , Herança Multifatorial , Humanos , Polimorfismo de Nucleotídeo Único
10.
Nutrients ; 11(7)2019 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-31261961

RESUMO

Taste and diet preferences are complex and influenced by both environmental and host traits while affecting both food selection and associated health outcomes. The present study genotyped 94 single nucleotide polymorphisms (SNPs) in previously reported taste and food intake related genes and assessed associations with taste threshold (TT) and preferred intensity (PT) of sweet, sour and bitter, food preferences, habitual diet intake, and caries status in healthy young Swedish men and women (n = 127). Polymorphisms in the GNAT3, SLC2A4, TAS1R1 and TAS1R2 genes were associated with variation in TT and PT for sweet taste as well as sweet food intake. Increasing PT for sweet was associated with increasing preference and intake of sugary foods. Similarly, increasing TT for sour was associated with increasing intake of sour foods, whereas the associations between food preference/intake and TT/PT for bitter was weak in this study group. Finally, allelic variation in the GNAT3, SLC2A2, SLC2A4, TAS1R1 and TAS1R2 genes was associated with caries status, whereas TT, PT and food preferences were not. It was concluded that variations in taste receptor, glucose transporter and gustducin encoding genes are related to taste perception, food preference and intake as well as the sugar-dependent caries disease.


Assuntos
Cárie Dentária/genética , Comportamento Alimentar , Polimorfismo de Nucleotídeo Único , Percepção Gustatória/genética , Paladar/genética , Adolescente , Cárie Dentária/diagnóstico , Feminino , Frequência do Gene , Predisposição Genética para Doença , Transportador de Glucose Tipo 2/genética , Transportador de Glucose Tipo 4/genética , Humanos , Masculino , Fenótipo , Receptores Acoplados a Proteínas-G/genética , Fatores de Risco , Suécia , Transducina/genética , Adulto Jovem
11.
Nat Commun ; 10(1): 2773, 2019 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-31235808

RESUMO

Dental caries and periodontitis account for a vast burden of morbidity and healthcare spending, yet their genetic basis remains largely uncharacterized. Here, we identify self-reported dental disease proxies which have similar underlying genetic contributions to clinical disease measures and then combine these in a genome-wide association study meta-analysis, identifying 47 novel and conditionally-independent risk loci for dental caries. We show that the heritability of dental caries is enriched for conserved genomic regions and partially overlapping with a range of complex traits including smoking, education, personality traits and metabolic measures. Using cardio-metabolic traits as an example in Mendelian randomization analysis, we estimate causal relationships and provide evidence suggesting that the processes contributing to dental caries may have undesirable downstream effects on health.


Assuntos
Cárie Dentária/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Periodontite/genética , Cárie Dentária/epidemiologia , Genômica , Hereditariedade , Humanos , Análise da Randomização Mendeliana , Periodontite/epidemiologia , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , Autorrelato/estatística & dados numéricos
12.
Nat Commun ; 10(1): 1052, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30837455

RESUMO

Mouth ulcers are the most common ulcerative condition and encompass several clinical diagnoses, including recurrent aphthous stomatitis (RAS). Despite previous evidence for heritability, it is not clear which specific genetic loci are implicated in RAS. In this genome-wide association study (n = 461,106) heritability is estimated at 8.2% (95% CI: 6.4%, 9.9%). This study finds 97 variants which alter the odds of developing non-specific mouth ulcers and replicate these in an independent cohort (n = 355,744) (lead variant after meta-analysis: rs76830965, near IL12A, OR 0.72 (95% CI: 0.71, 0.73); P = 4.4e-483). Additional effect estimates from three independent cohorts with more specific phenotyping and specific study characteristics support many of these findings. In silico functional analyses provide evidence for a role of T cell regulation in the aetiology of mouth ulcers. These results provide novel insight into the pathogenesis of a common, important condition.


Assuntos
Loci Gênicos/imunologia , Predisposição Genética para Doença , Fatores Imunológicos/genética , Úlceras Orais/genética , Estomatite Aftosa/genética , Adulto , Idoso , Estudos de Coortes , Simulação por Computador , Feminino , Estudo de Associação Genômica Ampla , Humanos , Fatores Imunológicos/imunologia , Masculino , Pessoa de Meia-Idade , Úlceras Orais/imunologia , Estomatite Aftosa/imunologia , Linfócitos T/imunologia
13.
Nat Commun ; 10(1): 357, 2019 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-30664637

RESUMO

Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences shaping these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic factors and low-frequency genetic variation. Here, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV + HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53, with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood, suggesting a previously unrecognized role of TP53 transcripts in human cranial development.


Assuntos
Alelos , Loci Gênicos , Variação Genética , RNA Mensageiro/genética , Crânio/metabolismo , Proteína Supressora de Tumor p53/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cefalometria , Criança , Grupo com Ancestrais do Continente Europeu , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Frequência do Gene , Genoma Humano , Humanos , Masculino , Pessoa de Meia-Idade , Crânio/anatomia & histologia
14.
Nat Commun ; 10(1): 333, 2019 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-30659178

RESUMO

Large studies use genotype data to discover genetic contributions to complex traits and infer relationships between those traits. Co-incident geographical variation in genotypes and health traits can bias these analyses. Here we show that single genetic variants and genetic scores composed of multiple variants are associated with birth location within UK Biobank and that geographic structure in genotype data cannot be accounted for using routine adjustment for study centre and principal components derived from genotype data. We find that major health outcomes appear geographically structured and that coincident structure in health outcomes and genotype data can yield biased associations. Understanding and accounting for this phenomenon will be important when making inference from genotype data in large studies.


Assuntos
Bancos de Espécimes Biológicos , Epidemiologia , Genótipo , Herança Multifatorial , Variação Genética , Estudo de Associação Genômica Ampla , Geografia , Humanos , Fenótipo , Gestantes , Alinhamento de Sequência , Reino Unido
16.
Hum Mol Genet ; 27(17): 3113-3127, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29931343

RESUMO

Prior studies suggest dental caries traits in children and adolescents are partially heritable, but there has been no large-scale consortium genome-wide association study (GWAS) to date. We therefore performed GWAS for caries in participants aged 2.5-18.0 years from nine contributing centres. Phenotype definitions were created for the presence or absence of treated or untreated caries, stratified by primary and permanent dentition. All studies tested for association between caries and genotype dosage and the results were combined using fixed-effects meta-analysis. Analysis included up to 19 003 individuals (7530 affected) for primary teeth and 13 353 individuals (5875 affected) for permanent teeth. Evidence for association with caries status was observed at rs1594318-C for primary teeth [intronic within ALLC, odds ratio (OR) 0.85, effect allele frequency (EAF) 0.60, P 4.13e-8] and rs7738851-A (intronic within NEDD9, OR 1.28, EAF 0.85, P 1.63e-8) for permanent teeth. Consortium-wide estimated heritability of caries was low [h2 of 1% (95% CI: 0%: 7%) and 6% (95% CI 0%: 13%) for primary and permanent dentitions, respectively] compared with corresponding within-study estimates [h2 of 28% (95% CI: 9%: 48%) and 17% (95% CI: 2%: 31%)] or previously published estimates. This study was designed to identify common genetic variants with modest effects which are consistent across different populations. We found few single variants associated with caries status under these assumptions. Phenotypic heterogeneity between cohorts and limited statistical power will have contributed; these findings could also reflect complexity not captured by our study design, such as genetic effects which are conditional on environmental exposure.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Biomarcadores/análise , Cárie Dentária/genética , Dentição Permanente , Estudo de Associação Genômica Ampla/métodos , Fosfoproteínas/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Fenótipo
17.
Community Dent Oral Epidemiol ; 46(6): 555-562, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29956852

RESUMO

OBJECTIVES: Counts of missing teeth or measures of incident tooth loss are gaining attention as a simple way to measure dental status in large population studies. We explore the meaning of these metrics and how missing teeth might influence other measures of dental status. METHODS: An observational study was performed in 2 contrasting adult populations. In total, 62 522 adult participants were available with clinically assessed caries and periodontal indices from the Swedish arm of the Gene-Lifestyle Interactions and Dental Endpoints Study (GLIDE) and the Korea National Health and Nutrition Examination Survey (KNHANES) in the Republic of Korea. Longitudinal measures of tooth loss were available for 28 244 participants in GLIDE with median follow-up of 10.6 years. RESULTS: In longitudinal analysis, hazard for tooth loss was associated with baseline dental status (previous tooth loss, periodontal status and caries status) and socio-demographic variables (age, smoking status and highest educational level). Analysis of cross-sectional data suggested that indices of caries exposure were not independent of periodontal status. The strength and direction of association varied between groups, even for measures specifically intended to avoid measuring tooth loss. Individuals with impaired periodontal health (community periodontal index [CPI] 3 or higher in any sextant) had higher standardized decayed and filled surfaces (DFS; number of DFS divided by total number of tooth surfaces) in GLIDE (incidence risk ratio [IRR] 1.05 [95% CI: 1.04, 1.07], but lower standardized DFS in KNHANES (IRR: 0.95 [0.92, 0.98]) than individuals with better periodontal health (CPI <3 in all sextants). CONCLUSIONS: Incident tooth loss is a complex measure of dental disease, with multiple determinants. The relative importance of dental caries and periodontal disease as drivers of tooth loss differs between age groups. Measures of dental caries exposure are associated with periodontal status in the studied populations, and these associations can be population-specific. Consideration of the study-specific properties of these metrics may be required for valid inference in large population studies.


Assuntos
Saúde Bucal , Perda de Dente/epidemiologia , Adulto , Índice CPO , Cárie Dentária/epidemiologia , Feminino , Nível de Saúde , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Doenças da Boca/diagnóstico , Doenças da Boca/epidemiologia , Inquéritos Nutricionais , Saúde Bucal/normas , Doenças Periodontais/epidemiologia , Índice Periodontal , República da Coreia , Perda de Dente/diagnóstico
18.
Wellcome Open Res ; 3: 34, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29806037

RESUMO

Oral health data in large longitudinal cohort studies is rarely collected at multiple time-points. This type of data is important for assessing oral health trajectories and their determinants. This data resource includes self-report questionnaire data on up to 4,222 young adults at approximately 23 years of age from the Avon Longitudinal Study of Parents and Children (ALSPAC). The resource includes questions on dental attendance, tooth restorations and extractions, third molars (wisdom teeth) and mouth ulcers. It follows on from similar questionnaires at ages 7, 10 and 17 years. The ALSPAC study includes extensive phenotype, genetic, epigenetic and metabolomic data from the participants included in this questionnaire plus their mothers and fathers.

19.
PLoS One ; 13(3): e0193504, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29561863

RESUMO

Bovine milk intake has been associated with various disease outcomes, with modulation of the gastro-intestinal microbiome being suggested as one potential mechanism. The aim of the present study was to explore the oral microbiota in relation to variation in self-reported milk intake. Saliva and tooth biofilm microbiota was characterized by 16S rDNA sequencing, PCR and cultivation in 154 Swedish adolescents, and information on diet and other lifestyle markers were obtained from a questionnaire, and dental caries from clinical examination. A replication cohort of 31,571 adults with similar information on diet intake, other lifestyle markers and caries was also studied. Multivariate partial least squares (PLS) modelling separated adolescents with low milk intake (lowest tertile with <0.4 servings/day) apart from those with high intake of milk (≥3.7 servings/day) based on saliva and tooth biofilm, respectively. Taxa in several genera contributed to this separation, and milk intake was inversely associated with the caries causing Streptococcus mutans in saliva and tooth biofilm samples by sequencing, PCR and cultivation. Despite the difference in S. mutans colonization, caries prevalence did not differ between milk consumption groups in the adolescents or the adults in the replication cohort, which may reflect that a significant positive association between intake of milk and sweet products was present in both the study and replication group. It was concluded that high milk intake correlates with different oral microbiota and it is hypothesized that milk may confer similar effects in the gut. The study also illustrated that reduction of one single disease associated bacterial species, such as S. mutans by milk intake, may modulate but not prevent development of complex diseases, such as caries, due to adverse effects from other causal factors, such as sugar intake in the present study.


Assuntos
Cárie Dentária/epidemiologia , Leite/efeitos adversos , Boca/microbiologia , Saliva/microbiologia , Autorrelato , Dente/microbiologia , Adolescente , Adulto , Animais , Biofilmes/crescimento & desenvolvimento , Bovinos , Estudos de Coortes , Cárie Dentária/microbiologia , Feminino , Humanos , Masculino , Microbiota , Prevalência , Suécia/epidemiologia
20.
Am J Hum Genet ; 101(2): 227-238, 2017 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-28757204

RESUMO

Vitamin D insufficiency is common, correctable, and influenced by genetic factors, and it has been associated with risk of several diseases. We sought to identify low-frequency genetic variants that strongly increase the risk of vitamin D insufficiency and tested their effect on risk of multiple sclerosis, a disease influenced by low vitamin D concentrations. We used whole-genome sequencing data from 2,619 individuals through the UK10K program and deep-imputation data from 39,655 individuals genotyped genome-wide. Meta-analysis of the summary statistics from 19 cohorts identified in CYP2R1 the low-frequency (minor allele frequency = 2.5%) synonymous coding variant g.14900931G>A (p.Asp120Asp) (rs117913124[A]), which conferred a large effect on 25-hydroxyvitamin D (25OHD) levels (-0.43 SD of standardized natural log-transformed 25OHD per A allele; p value = 1.5 × 10-88). The effect on 25OHD was four times larger and independent of the effect of a previously described common variant near CYP2R1. By analyzing 8,711 individuals, we showed that heterozygote carriers of this low-frequency variant have an increased risk of vitamin D insufficiency (odds ratio [OR] = 2.2, 95% confidence interval [CI] = 1.78-2.78, p = 1.26 × 10-12). Individuals carrying one copy of this variant also had increased odds of multiple sclerosis (OR = 1.4, 95% CI = 1.19-1.64, p = 2.63 × 10-5) in a sample of 5,927 case and 5,599 control subjects. In conclusion, we describe a low-frequency CYP2R1 coding variant that exerts the largest effect upon 25OHD levels identified to date in the general European population and implicates vitamin D in the etiology of multiple sclerosis.


Assuntos
Colestanotriol 26-Mono-Oxigenase/genética , Família 2 do Citocromo P450/genética , Predisposição Genética para Doença/genética , Esclerose Múltipla/genética , Deficiência de Vitamina D/diagnóstico , Deficiência de Vitamina D/genética , Vitamina D/análogos & derivados , Frequência do Gene , Genoma Humano/genética , Estudo de Associação Genômica Ampla , Humanos , Esclerose Múltipla/etiologia , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Vitamina D/sangue
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