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1.
mSystems ; 5(5)2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-32994293

RESUMO

One of the strongest associations between human genetics and the gut microbiome is a greater relative abundance of Bifidobacterium in adults with lactase gene (LCT) single nucleotide polymorphisms (SNPs) associated with lactase nonpersistence (GG genotypes), versus lactase persistence (AA/AG genotypes). To gain a finer-grained phylogenetic resolution of this association, we interrogated 1,680 16S rRNA libraries and 245 metagenomes from gut microbiomes of adults with various lactase persistence genotypes. We further employed a novel genome-capture-based enrichment of Bifidobacterium DNA from a subset of these metagenomes, including monozygotic (MZ) twin pairs, each sampled 2 or 3 times. B. adolescentis and B. longum were the most abundant Bifidobacterium species regardless of host LCT genotype. LCT genotypes could not be discriminated based on relative abundances of Bifidobacterium species or Bifidobacterium community structure. Three distinct metagenomic analysis methods of Bifidobacterium-enriched DNA revealed intraindividual temporal stability of B. longum, B. adolescentis, and B. bifidum strains against the background of a changeable microbiome. Two of our three methods also observed greater strain sharing within MZ twin pairs than within unrelated individuals for B. adolescentis, while no method revealed an effect of host LCT genotype on Bifidobacterium strain composition. Our results support a "rising tide lifts all boats" model for the dominant bifidobacteria in the adult gut: their higher abundance in lactase-nonpersistent than in lactase-persistent individuals results from an expansion at the genus level. Bifidobacterium species are known to be transmitted from mother to child and stable within individuals in infancy and childhood: our results extend this stability into adulthood.IMPORTANCE When humans domesticated animals, some adapted genetically to digest milk into adulthood (lactase persistence). The gut microbiomes of people with lactase-persistent genotypes (AA or AG) differ from those with lactase-nonpersistent genotypes (GG) by containing fewer bacteria belonging to the bifidobacteria, a group which contains beneficial species. Here, we asked if the gut microbiomes of adults with GG and AA/AG genotypes differ in the species of bifidobacteria present. In particular, we used a novel technique which allowed us to compare bifidobacteria in adults at the strain level, without the traditional need for culturing. Our results show that the GG genotype enhances the abundance of bifidobacteria regardless of species. We also noted that a person's specific strains are recoverable several years later, and twins can share the same ones. Given that bifidobacteria are inherited from mother to child, strain stability over time in adulthood suggests long-term, multigenerational inheritance.

2.
Neurogastroenterol Motil ; 32(11): e13939, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32715594

RESUMO

BACKGROUND: The aetiology of irritable bowel syndrome (IBS) is multifactorial, including genetic and environmental factors. Previous studies have suggested that low birth weight and family environment during childhood are associated with developing IBS. METHODS: A survey was sent to all individuals in a UK twin registry. Questions included IBS diagnosed by the Rome IV criteria and if a doctor had previously diagnosed them with IBS. Subjects were categorized as having IBS by Rome IV criteria, a medical diagnosis of IBS or no IBS. Further questions included subjects' recollections of their parents' responses to illness in both the respondent as a child and in the parents themselves. Information regarding birth weight and gestational age have been collected previously. KEY RESULTS: 4258 subjects responded to the questionnaire (51.7%), mean age of 52 (SD 14) years, of whom 98.5% were white and 89.6% female. The mean birth weight was 2.4  (0.6) kg. 5.1% satisfied the Rome IV IBS criteria, the same prevalence as the UK population. However, 14.1% had a previous medical diagnosis of IBS. There was no association found between birth weight and IBS or a medical diagnosis of IBS. On multivariable regression analysis, including parental responses to illness, subjects recalling a parent responding to the parent's bowel symptoms by excusing themselves from household chores were associated with a Rome IV diagnosis of IBS (OR 2.19 (95% CI 1.17-4.10), P = .013). CONCLUSIONS AND INFERENCES: There was no association between birth weight and IBS. However, observing their parents excuse themselves from household chores when they had bowel symptoms was associated with IBS in later life.

3.
Hum Mol Genet ; 29(5): 864-875, 2020 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-31960908

RESUMO

Saliva, as a biofluid, is inexpensive and non-invasive to obtain, and provides a vital tool to investigate oral health and its interaction with systemic health conditions. There is growing interest in salivary biomarkers for systemic diseases, notably cardiovascular disease. Whereas hundreds of genetic loci have been shown to be involved in the regulation of blood metabolites, leading to significant insights into the pathogenesis of complex human diseases, little is known about the impact of host genetics on salivary metabolites. Here we report the first genome-wide association study exploring 476 salivary metabolites in 1419 subjects from the TwinsUK cohort (discovery phase), followed by replication in the Study of Health in Pomerania (SHIP-2) cohort. A total of 14 distinct locus-metabolite associations were identified in the discovery phase, most of which were replicated in SHIP-2. While only a limited number of the loci that are known to regulate blood metabolites were also associated with salivary metabolites in our study, we identified several novel saliva-specific locus-metabolite associations, including associations for the AGMAT (with the metabolites 4-guanidinobutanoate and beta-guanidinopropanoate), ATP13A5 (with the metabolite creatinine) and DPYS (with the metabolites 3-ureidopropionate and 3-ureidoisobutyrate) loci. Our study suggests that there may be regulatory pathways of particular relevance to the salivary metabolome. In addition, some of our findings may have clinical significance, such as the utility of the pyrimidine (uracil) degradation metabolites in predicting 5-fluorouracil toxicity and the role of the agmatine pathway metabolites as biomarkers of oral health.

4.
Genome Med ; 12(1): 7, 2020 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-31924279

RESUMO

BACKGROUND: Modern medicine is rapidly moving towards a data-driven paradigm based on comprehensive multimodal health assessments. Integrated analysis of data from different modalities has the potential of uncovering novel biomarkers and disease signatures. METHODS: We collected 1385 data features from diverse modalities, including metabolome, microbiome, genetics, and advanced imaging, from 1253 individuals and from a longitudinal validation cohort of 1083 individuals. We utilized a combination of unsupervised machine learning methods to identify multimodal biomarker signatures of health and disease risk. RESULTS: Our method identified a set of cardiometabolic biomarkers that goes beyond standard clinical biomarkers. Stratification of individuals based on the signatures of these biomarkers identified distinct subsets of individuals with similar health statuses. Subset membership was a better predictor for diabetes than established clinical biomarkers such as glucose, insulin resistance, and body mass index. The novel biomarkers in the diabetes signature included 1-stearoyl-2-dihomo-linolenoyl-GPC and 1-(1-enyl-palmitoyl)-2-oleoyl-GPC. Another metabolite, cinnamoylglycine, was identified as a potential biomarker for both gut microbiome health and lean mass percentage. We identified potential early signatures for hypertension and a poor metabolic health outcome. Additionally, we found novel associations between a uremic toxin, p-cresol sulfate, and the abundance of the microbiome genera Intestinimonas and an unclassified genus in the Erysipelotrichaceae family. CONCLUSIONS: Our methodology and results demonstrate the potential of multimodal data integration, from the identification of novel biomarker signatures to a data-driven stratification of individuals into disease subtypes and stages-an essential step towards personalized, preventative health risk assessment.

6.
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
7.
Twin Res Hum Genet ; 22(6): 523-529, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31526404

RESUMO

TwinsUK is the largest cohort of community-dwelling adult twins in the UK. The registry comprises over 14,000 volunteer twins (14,838 including mixed, single and triplets); it is predominantly female (82%) and middle-aged (mean age 59). In addition, over 1800 parents and siblings of twins are registered volunteers. During the last 27 years, TwinsUK has collected numerous questionnaire responses, physical/cognitive measures and biological measures on over 8500 subjects. Data were collected alongside four comprehensive phenotyping clinical visits to the Department of Twin Research and Genetic Epidemiology, King's College London. Such collection methods have resulted in very detailed longitudinal clinical, biochemical, behavioral, dietary and socioeconomic cohort characterization; it provides a multidisciplinary platform for the study of complex disease during the adult life course, including the process of healthy aging. The major strength of TwinsUK is the availability of several 'omic' technologies for a range of sample types from participants, which includes genomewide scans of single-nucleotide variants, next-generation sequencing, metabolomic profiles, microbiomics, exome sequencing, epigenetic markers, gene expression arrays, RNA sequencing and telomere length measures. TwinsUK facilitates and actively encourages sharing the 'TwinsUK' resource with the scientific community - interested researchers may request data via the TwinsUK website (http://twinsuk.ac.uk/resources-for-researchers/access-our-data/) for their own use or future collaboration with the study team. In addition, further cohort data collection is planned via the Wellcome Open Research gateway (https://wellcomeopenresearch.org/gateways). The current article presents an up-to-date report on the application of technological advances, new study procedures in the cohort and future direction of TwinsUK.


Assuntos
Doenças em Gêmeos/epidemiologia , Marcadores Genéticos , Metaboloma , Metagenoma , Sistema de Registros/estatística & dados numéricos , Gêmeos/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças em Gêmeos/genética , Doenças em Gêmeos/metabolismo , Doenças em Gêmeos/microbiologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Incidência , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Reino Unido/epidemiologia , Adulto Jovem
9.
Arthritis Rheumatol ; 71(10): 1642-1650, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31038287

RESUMO

OBJECTIVE: HLA alleles affect susceptibility to more than 100 diseases, but the mechanisms that account for these genotype-disease associations are largely unknown. HLA alleles strongly influence predisposition to ankylosing spondylitis (AS) and rheumatoid arthritis (RA). Both AS and RA patients have discrete intestinal and fecal microbiome signatures. Whether these changes are the cause or consequence of the diseases themselves is unclear. To distinguish these possibilities, we examined the effect of HLA-B27 and HLA-DRB1 RA risk alleles on the composition of the intestinal microbiome in healthy individuals. METHODS: Five hundred sixty-eight stool and biopsy samples from 6 intestinal sites were collected from 107 healthy unrelated subjects, and stool samples were collected from 696 twin pairs from the TwinsUK cohort. Microbiome profiling was performed using sequencing of the 16S ribosomal RNA bacterial marker gene. All subjects were genotyped using the Illumina CoreExome SNP microarray, and HLA genotypes were imputed from these data. RESULTS: Associations were observed between the overall microbial composition and both the HLA-B27 genotype and the HLA-DRB1 RA risk allele (P = 0.0002 and P = 0.00001, respectively). These associations were replicated using the stool samples from the TwinsUK cohort (P = 0.023 and P = 0.033, respectively). CONCLUSION: This study shows that the changes in intestinal microbiome composition seen in AS and RA are at least partially due to effects of HLA-B27 and HLA-DRB1 on the gut microbiome. These findings support the hypothesis that HLA alleles operate to cause or increase the risk of these diseases through interaction with the intestinal microbiome and suggest that therapies targeting the microbiome may be effective in preventing or treating these diseases.


Assuntos
Artrite Reumatoide/genética , Microbioma Gastrointestinal/genética , Antígeno HLA-B27/genética , Cadeias HLA-DRB1/genética , Espondilite Anquilosante/genética , Adulto , Idoso , Alelos , Artrite Reumatoide/microbiologia , Estudos de Coortes , Feminino , Humanos , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-Idade , RNA Ribossômico 16S/genética , Espondilite Anquilosante/microbiologia
10.
J Bone Miner Res ; 34(7): 1284-1296, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30888730

RESUMO

Hip geometry is an important predictor of fracture. We performed a meta-analysis of GWAS studies in adults to identify genetic variants that are associated with proximal femur geometry phenotypes. We analyzed four phenotypes: (i) femoral neck length; (ii) neck-shaft angle; (iii) femoral neck width, and (iv) femoral neck section modulus, estimated from DXA scans using algorithms of hip structure analysis. In the Discovery stage, 10 cohort studies were included in the fixed-effect meta-analysis, with up to 18,719 men and women ages 16 to 93 years. Association analyses were performed with ∼2.5 million polymorphisms under an additive model adjusted for age, body mass index, and height. Replication analyses of meta-GWAS significant loci (at adjusted genomewide significance [GWS], threshold p ≤ 2.6 × 10-8 ) were performed in seven additional cohorts in silico. We looked up SNPs associated in our analysis, for association with height, bone mineral density (BMD), and fracture. In meta-analysis (combined Discovery and Replication stages), GWS associations were found at 5p15 (IRX1 and ADAMTS16); 5q35 near FGFR4; at 12p11 (in CCDC91); 11q13 (near LRP5 and PPP6R3 (rs7102273)). Several hip geometry signals overlapped with BMD, including LRP5 (chr. 11). Chr. 11 SNP rs7102273 was associated with any-type fracture (p = 7.5 × 10-5 ). We used bone transcriptome data and discovered several significant eQTLs, including rs7102273 and PPP6R3 expression (p = 0.0007), and rs6556301 (intergenic, chr.5 near FGFR4) and PDLIM7 expression (p = 0.005). In conclusion, we found associations between several genes and hip geometry measures that explained 12% to 22% of heritability at different sites. The results provide a defined set of genes related to biological pathways relevant to BMD and etiology of bone fragility. © 2019 American Society for Bone and Mineral Research.


Assuntos
Variação Genética , Estudo de Associação Genômica Ampla , Ossos Pélvicos/anatomia & histologia , Adulto , Animais , Células Cultivadas , Osso Cortical/metabolismo , Epigênese Genética , Feminino , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Fraturas do Quadril/genética , Humanos , Desequilíbrio de Ligação/genética , Masculino , Camundongos , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes
11.
Cell Host Microbe ; 25(2): 261-272.e5, 2019 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-30763537

RESUMO

The virome is one of the most variable components of the human gut microbiome. Within twin pairs, viromes have been shown to be similar for infants, but not for adults, indicating that as twins age and their environments and microbiomes diverge, so do their viromes. The degree to which the microbiome drives the vast virome diversity is unclear. Here, we examine the relationship between microbiome and virome diversity in 21 adult monozygotic twin pairs selected for high or low microbiome concordance. Viromes derived from virus-like particles are unique to each individual, are dominated by Caudovirales and Microviridae, and exhibit a small core that includes crAssphage. Microbiome-discordant twins display more dissimilar viromes compared to microbiome-concordant twins, and the richer the microbiomes, the richer the viromes. These patterns are driven by bacteriophages, not eukaryotic viruses. Collectively, these observations support a strong role of the microbiome in patterning for the virome.


Assuntos
DNA Bacteriano/genética , DNA Viral/genética , Microbioma Gastrointestinal/genética , Variação Genética/genética , Gêmeos Monozigóticos , Adulto , Sequência de Bases , Fezes/microbiologia , Fezes/virologia , Microbioma Gastrointestinal/fisiologia , Humanos , Filogenia , RNA Ribossômico 16S/genética , Alinhamento de Sequência
14.
PLoS Genet ; 14(12): e1007813, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30566500

RESUMO

Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Affected women frequently have metabolic disturbances including insulin resistance and dysregulation of glucose homeostasis. PCOS is diagnosed with two different sets of diagnostic criteria, resulting in a phenotypic spectrum of PCOS cases. The genetic similarities between cases diagnosed based on the two criteria have been largely unknown. Previous studies in Chinese and European subjects have identified 16 loci associated with risk of PCOS. We report a fixed-effect, inverse-weighted-variance meta-analysis from 10,074 PCOS cases and 103,164 controls of European ancestry and characterisation of PCOS related traits. We identified 3 novel loci (near PLGRKT, ZBTB16 and MAPRE1), and provide replication of 11 previously reported loci. Only one locus differed significantly in its association by diagnostic criteria; otherwise the genetic architecture was similar between PCOS diagnosed by self-report and PCOS diagnosed by NIH or non-NIH Rotterdam criteria across common variants at 13 loci. Identified variants were associated with hyperandrogenism, gonadotropin regulation and testosterone levels in affected women. Linkage disequilibrium score regression analysis revealed genetic correlations with obesity, fasting insulin, type 2 diabetes, lipid levels and coronary artery disease, indicating shared genetic architecture between metabolic traits and PCOS. Mendelian randomization analyses suggested variants associated with body mass index, fasting insulin, menopause timing, depression and male-pattern balding play a causal role in PCOS. The data thus demonstrate 3 novel loci associated with PCOS and similar genetic architecture for all diagnostic criteria. The data also provide the first genetic evidence for a male phenotype for PCOS and a causal link to depression, a previously hypothesized comorbid disease. Thus, the genetics provide a comprehensive view of PCOS that encompasses multiple diagnostic criteria, gender, reproductive potential and mental health.


Assuntos
Síndrome do Ovário Policístico/diagnóstico , Síndrome do Ovário Policístico/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Fenótipo
15.
Nat Commun ; 9(1): 5075, 2018 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-30542056

RESUMO

Acne vulgaris is a highly heritable common, chronic inflammatory disease of the skin for which five genetic risk loci have so far been identified. Here, we perform a genome-wide association study of 3823 cases and 16,144 controls followed by meta-analysis with summary statistics from a previous study, with a total sample size of 26,722. We identify 20 independent association signals at 15 risk loci, 12 of which have not been previously implicated in the disease. Likely causal variants disrupt the coding region of WNT10A and a P63 transcription factor binding site in SEMA4B. Risk alleles at the 1q25 locus are associated with increased expression of LAMC2, in which biallelic loss-of-function mutations cause the blistering skin disease epidermolysis bullosa. These findings indicate that variation affecting the structure and maintenance of the skin, in particular the pilosebaceous unit, is a critical aspect of the genetic predisposition to severe acne.


Assuntos
Acne Vulgar/genética , Acne Vulgar/patologia , Predisposição Genética para Doença/genética , Folículo Piloso/crescimento & desenvolvimento , Feminino , Variação Genética/genética , Estudo de Associação Genômica Ampla , Infecções por Bactérias Gram-Positivas/microbiologia , Infecções por Bactérias Gram-Positivas/patologia , Humanos , Laminina/biossíntese , Laminina/genética , Masculino , Proteínas de Membrana/metabolismo , Propionibacterium acnes/crescimento & desenvolvimento , Semaforinas/genética , Pele/patologia , Proteínas Wnt/genética
16.
Nat Commun ; 9(1): 4774, 2018 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-30429480

RESUMO

The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, UK, and USA comprising 52,506 individuals. We confirm known loci including MTAP, PLA2G6, and IRF4, and detect novel SNPs in KITLG and a region of 9q32. In a bivariate analysis combining the nevus results with a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1, PPARGC1B, HDAC4, FAM208B, DOCK8, and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level. Overall, we conclude that most nevus genes affect melanoma risk (KITLG an exception), while many melanoma risk loci do not alter nevus count. For example, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis.


Assuntos
Grupo com Ancestrais do Continente Europeu/genética , Pleiotropia Genética/genética , Melanoma/genética , Nevo Pigmentado/genética , Neoplasias Cutâneas/genética , Proteínas de Transporte/genética , Citocromo P-450 CYP1B1/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Fosfolipases A2 do Grupo VI/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Histona Desacetilases/genética , Humanos , Fatores Reguladores de Interferon/genética , MicroRNAs/genética , Proteínas dos Microfilamentos/genética , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único , RNA/genética , Proteínas de Ligação a RNA , Receptores Acoplados a Proteínas-G/genética , Proteínas Repressoras/genética , Fator de Células-Tronco/genética , Telomerase/genética , Proteínas de Ligação a Telômeros/genética
17.
BMC Microbiol ; 18(1): 114, 2018 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-30208875

RESUMO

BACKGROUND: Asthma, one of the most common chronic respiratory disorders, is associated with the hyper-activation of the T-cell subset of adaptive immunity. The gut microbiota may be involved in the development of asthma through the production of short-chain fatty acids (SCFAs), exhibiting modulatory effects on Th. So, we performed a metagenome-wide association study (MWAS) of the fecal microbiota from individuals with asthma and healthy controls. And that was the first case to resolve the relationship between asthma and microbiome among UK adults. RESULTS: The microbiota of the individuals with asthma consisted of fewer microbial entities than the microbiota of healthy individuals. Faecalibacterium prausnitzii, Sutterella wadsworthensis and Bacteroides stercoris were depleted in cases, whereas Clostridiums with Eggerthella lenta were over-represented in individuals with asthma. Functional analysis shows that the SCFAs might be altered in the microbiota of asthma patients. CONCLUSION: In all, the adult human gut microbiome of asthma patients is clearly different from healthy controls. The functional and taxa results showed that the change of asthma patients might related to SCFAs.


Assuntos
Asma/microbiologia , Bactérias/isolamento & purificação , Microbioma Gastrointestinal , Adulto , Bactérias/classificação , Bactérias/genética , Bactérias/metabolismo , Ácidos Graxos Voláteis/metabolismo , Fezes/microbiologia , Feminino , Humanos , Intestinos/microbiologia , Masculino , Metagenoma , Reino Unido
18.
Genes (Basel) ; 9(5)2018 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-29758014

RESUMO

Monozygotic (MZ) twins are typically indistinguishable via forensic DNA profiling. Recently, we demonstrated that epigenetic differentiation of MZ twins is feasible; however, proportions of twin differentially methylated CpG sites (tDMSs) identified in reference-type blood DNA were not replicated in trace-type blood DNA. Here we investigated buccal swabs as typical forensic reference material, and saliva and cigarette butts as commonly encountered forensic trace materials. As an analog to a forensic case, we analyzed one MZ twin pair. Epigenome-wide microarray analysis in reference-type buccal DNA revealed 25 candidate tDMSs with >0.5 twin-to-twin differences. MethyLight quantitative PCR (qPCR) of 22 selected tDMSs in trace-type DNA revealed in saliva DNA that six tDMSs (27.3%) had >0.1 twin-to-twin differences, seven (31.8%) had smaller (<0.1) but robustly detected differences, whereas for nine (40.9%) the differences were in the opposite direction relative to the microarray data; for cigarette butt DNA, results were 50%, 22.7%, and 27.3%, respectively. The discrepancies between reference-type and trace-type DNA outcomes can be explained by cell composition differences, method-to-method variation, and other technical reasons including bisulfite conversion inefficiency. Our study highlights the importance of the DNA source and that careful characterization of biological and technical effects is needed before epigenetic MZ twin differentiation is applicable in forensic casework.

19.
Nat Genet ; 50(5): 652-656, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29662168

RESUMO

Hair color is one of the most recognizable visual traits in European populations and is under strong genetic control. Here we report the results of a genome-wide association study meta-analysis of almost 300,000 participants of European descent. We identified 123 autosomal and one X-chromosome loci significantly associated with hair color; all but 13 are novel. Collectively, single-nucleotide polymorphisms associated with hair color within these loci explain 34.6% of red hair, 24.8% of blond hair, and 26.1% of black hair heritability in the study populations. These results confirm the polygenic nature of complex phenotypes and improve our understanding of melanin pigment metabolism in humans.


Assuntos
Grupo com Ancestrais do Continente Europeu/genética , Loci Gênicos , Cor de Cabelo/genética , Herança Multifatorial , Polimorfismo de Nucleotídeo Único/genética , Idoso , Cromossomos Humanos X , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo
20.
Int J Epidemiol ; 47(3): 908-916, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29518222

RESUMO

BACKGROUND: Investigating the genetic and environmental causes of variation in genome-wide average DNA methylation (GWAM), a global methylation measure from the HumanMethylation450 array, might give a better understanding of genetic and environmental influences on methylation. METHODS: We measured GWAM for 2299 individuals aged 0 to 90 years from seven twin and/or family studies. We estimated familial correlations, modelled correlations with cohabitation history and fitted variance components models for GWAM. RESULTS: The correlation in GWAM for twin pairs was ∼0.8 at birth, decreased with age during adolescence and was constant at ∼0.4 throughout adulthood, with no evidence that twin pair correlations differed by zygosity. Non-twin first-degree relatives were correlated, from 0.17 [95% confidence interval (CI): 0.05-0.30] to 0.28 (95% CI: 0.08-0.48), except for middle-aged siblings (0.01, 95% CI: -0.10-0.12), and the correlation increased with time living together and decreased with time living apart. Spouse pairs were correlated in all studies, from 0.23 (95% CI: 0.3-0.43) to 0.31 (95% CI: 0.05-0.52), and the correlation increased with time living together. The variance explained by environmental factors shared by twins alone was 90% (95% CI: 74-95%) at birth, decreased in early life and plateaued at 28% (95% CI: 17-39%) in middle age and beyond. There was a cohabitation-related environmental component of variance. CONCLUSIONS: GWAM is determined in utero by prenatal environmental factors, the effects of which persist throughout life. The variation of GWAM is also influenced by environmental factors shared by family members, as well as by individual-specific environmental factors.

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