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1.
Nat Commun ; 10(1): 2094, 2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-31064978

RESUMO

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system with a modest concordance rate in monozygotic twins, which strongly argues for involvement of epigenetic factors. We observe highly similar peripheral blood mononuclear cell-based methylomes in 45 MS-discordant monozygotic twins. Nevertheless, we identify seven MS-associated differentially methylated positions (DMPs) of which we validate two, including a region in the TMEM232 promoter and ZBTB16 enhancer. In CD4 + T cells we find an MS-associated differentially methylated region in FIRRE. Additionally, 45 regions show large methylation differences in individual pairs, but they do not clearly associate with MS. Furthermore, we present epigenetic biomarkers for current interferon-beta treatment, and extensive validation shows that the ZBTB16 DMP is a signature for prior glucocorticoid treatment. Taken together, this study represents an important reference for epigenomic MS studies, identifies new candidate epigenetic markers, and highlights treatment effects and genetic background as major confounders.


Assuntos
Metilação de DNA/genética , Doenças em Gêmeos/genética , Epigênese Genética , Predisposição Genética para Doença , Esclerose Múltipla/genética , Adulto , Idoso , Biomarcadores , Doenças em Gêmeos/sangue , Elementos Facilitadores Genéticos/genética , Epigenômica/métodos , Feminino , Humanos , Leucócitos Mononucleares , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Regiões Promotoras Genéticas/genética , Proteína com Dedos de Zinco da Leucemia Promielocítica/genética , RNA Longo não Codificante/genética , Gêmeos Monozigóticos , Adulto Jovem
2.
Zhonghua Liu Xing Bing Xue Za Zhi ; 40(4): 389-393, 2019 Apr 10.
Artigo em Chinês | MEDLINE | ID: mdl-31006196

RESUMO

Objective: To analyze the heritability of diabetes among the Chinese twin adults. Methods: A total of 10 253 same-sex twin pairs aged 25 years and older, were selected from the Chinese National Twin Registry (CNTR) program. Heritability of diabetes was calculated by using the structural equation model. Results: After adjusted for age and gender, the overall heritability rates of diabetes were 0.41 (0.15-0.75), 0.83 (0.72-0.91) and 0.34 (0.04-0.73) in the <45 and ≥45 years twin pairs, respectively. After adjusted for age, rates of heritability appeared as 0.37 (0.05-0.78) and 0.88 (0.79-0.94) in men and women, respectively. Conclusions: Diabetes is affected by both genetic and environmental factors. The genetic effect of diabetes seemed stronger on female than that on male twins but was dying down along with ageing.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Diabetes Mellitus/genética , Gêmeos Monozigóticos , Adulto , Diabetes Mellitus/etnologia , Doenças em Gêmeos/etnologia , Doenças em Gêmeos/genética , Feminino , Humanos , Masculino
3.
Pediatrics ; 143(5)2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31028158

RESUMO

OBJECTIVES: To explore the relative contributions of genetic and environmental influences on dental caries risk and to investigate fetal and developmental risk factors for dental caries. METHODS: We recruited children from 250 twin pregnancies midgestation and collected demographic, health, and phenotypic data at recruitment, 24 and 36 weeks' gestational age, birth and 18 months, and 6 years of age. 25-hydroxyvitamin D was quantified in mothers at 28 weeks' gestation and in infants at birth. Dental caries and enamel defects were measured at six years of age. We compared concordance for the presence of any caries and advanced caries in monozygotic and dizygotic twin pairs. To investigate environmental risk factors for caries, we fitted multiple logistic regression models using generalized estimating equations to adjust for twin correlation. RESULTS: A total of 345 twins underwent dental assessment, with 111 (32.2%) showing signs of any caries and 83 (24.1%) having advanced caries. There was no evidence of higher concordance in monozygotic twins compared with dizygotic twins, with a difference of 0.05 (95% confidence interval -0.14 to 0.25; P = .30) and 0.00 (95% confidence interval -0.26 to 0.26; P = .50) for any caries and advanced caries, respectively, suggesting that environmental factors, rather than genetics, are the predominant determinant of caries risk. After adjusting for potential confounders, lack of community water fluoridation, hypomineralized second primary molars, dichorionic placenta, and maternal obesity were associated with caries. CONCLUSIONS: Environmental rather than genetic factors drive dental caries risk and arise as early as prenatal life.


Assuntos
Cárie Dentária/epidemiologia , Cárie Dentária/genética , Doenças em Gêmeos/epidemiologia , Doenças em Gêmeos/genética , Meio Ambiente , Interação Gene-Ambiente , Criança , Cárie Dentária/sangue , Doenças em Gêmeos/sangue , Feminino , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Gravidez , Estudos Prospectivos , Fatores de Risco , Vitamina D/análogos & derivados , Vitamina D/sangue
4.
Clin Epigenetics ; 11(1): 27, 2019 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-30760334

RESUMO

BACKGROUND: Genetic and environmental risk factors contribute to periodontal disease, but the underlying susceptibility pathways are not fully understood. Epigenetic mechanisms are malleable regulators of gene function that can change in response to genetic and environmental stimuli, thereby providing a potential mechanism for mediating risk effects in periodontitis. The aim of this study is to identify epigenetic changes across tissues that are associated with periodontal disease. METHODS: Self-reported gingival bleeding and history of gum disease, or tooth mobility, were used as indicators of periodontal disease. DNA methylation profiles were generated using the Infinium HumanMethylation450 BeadChip in whole blood, buccal, and adipose tissue samples from predominantly older female twins (mean age 58) from the TwinsUK cohort. Epigenome-wide association scans (EWAS) of gingival bleeding and tooth mobility were conducted in whole blood in 528 and 492 twins, respectively. Subsequently, targeted candidate gene analysis at 28 genomic regions was carried out testing for phenotype-methylation associations in 41 (tooth mobility) and 43 (gingival bleeding) buccal, and 501 (tooth mobility) and 556 (gingival bleeding) adipose DNA samples. RESULTS: Epigenome-wide analyses in blood identified one CpG-site (cg21245277 in ZNF804A) associated with gingival bleeding (FDR = 0.03, nominal p value = 7.17e-8) and 58 sites associated with tooth mobility (FDR < 0.05) with the top signals in IQCE and XKR6. Epigenetic variation at 28 candidate regions (247 CpG-sites) for chronic periodontitis showed an enrichment for association with periodontal traits, and signals in eight genes (VDR, IL6ST, TMCO6, IL1RN, CD44, IL1B, WHAMM, and CXCL1) were significant in both traits. The methylation-phenotype association signals validated in buccal samples, and a subset (25%) also validated in adipose tissue. CONCLUSIONS: Epigenome-wide analyses in adult female twins identified specific DNA methylation changes linked to self-reported periodontal disease. Future work will explore the environmental basis and functional impact of these results to infer potential for strategic personalized treatments and prevention of chronic periodontitis.


Assuntos
Metilação de DNA , Doenças em Gêmeos/genética , Estudo de Associação Genômica Ampla/métodos , Periodontite/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Ilhas de CpG , Estudos Transversais , Epigênese Genética , Feminino , Humanos , Pessoa de Meia-Idade , Fenótipo , Análise de Sequência de RNA/métodos , Reino Unido
5.
Acta Ophthalmol ; 97(6): 603-607, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30702215

RESUMO

PURPOSE: To examine genetic influences on interocular similarities in ocular refraction and components of refraction among elderly female twins. METHODS: Refraction was assessed in 94 monozygotic (MZ) and 74 dizygotic (DZ) female twins aged 66-78 years. Absolute values of interocular differences (Aniso variables) in spherical refraction (SR), refractive astigmatism (AST), spherical equivalent (SE), corneal refractive power (CR), corneal astigmatism (CAST), anterior chamber depth (ACD) and axial length (AL) were calculated. The differences between sisters in each of the Aniso variables were calculated and graded into two categories, best differentiating the groups, here isometropic and anisometropic values. The cut-offs for grading as isometropic were AnisoSR < 0.75 D, AnisoAST < 0.5 D, AnisoSE < 1.0 D, AnisoCR < 0.5 D, AnisoCAST < 0.50 D, AnisoACD < 0.1 mm and AniosAL < 0.1 mm. Genetic influences on these traits were investigated by comparing the prevalence of isometropic and anisometropic differences between the MZ and DZ pairs in the Aniso variables and the interrelationships between the Aniso variables. RESULTS: When the Aniso variables were treated as continuous, no significant differences were found between the MZ and DZ subjects. When the proportions of isometropic intratwinpair interocular differences in the Aniso variables in the MZ and DZ cotwins were compared, the prevalences (MZ/DZ) were AnisoSR: 68%/60%; AnisoAST: 66%/57%; AnisoSE: 87%/68%; AnisoCR: 83%/78%; AnisoCAST: 69%/35%; AnisoACD: 77%/63%; and AnisoAL: 76%/60%. The differences were statistically significant for Aniso SE (p = 0.035, Fisher's exact test) and CAST (p = 0.007). The greater homogeneity in the interocular differences between the MZ sisters supports the assumption that isometropia of different elements of refraction is genetically influenced and tending to continue up to older ages. In cases where AnisoSE was <1.0 D, higher CR in one eye was associated with shorter AL (r = -0.398, p < 0.001), thereby contributing to emmetropization, irrespective of zygosity. In the cases of AnisoSE ≥1 D, no similar influence on emmetropization was observed. The difference between sisters in AnisoSE was associated with the intratwinpair difference in Aniso AL, but not with the intratwinpair differences in AnisoCR, irrespective of zygosity. CONCLUSION: The higher prevalence of similarities in isometropia of the spherical equivalent and corneal astigmatism between the MZ pairs compared to DZ pairs is consistent with the view that genetic influences on the refractive elements of the eye, tending to isometropia, continue into older age. The interrelation between CR and AL tends to maintain isometropia of SE irrespective of zygosity.


Assuntos
Córnea/fisiopatologia , Doenças em Gêmeos/genética , Predisposição Genética para Doença , Refração Ocular/fisiologia , Erros de Refração/genética , Idoso , Biometria , Feminino , Humanos , Erros de Refração/fisiopatologia , Gêmeos Dizigóticos , Gêmeos Monozigóticos
6.
Zhonghua Fu Chan Ke Za Zhi ; 54(2): 87-92, 2019 Feb 25.
Artigo em Chinês | MEDLINE | ID: mdl-30803166

RESUMO

Objective: To analyze the clinical characteristics of structural malformations in one of monochorionic diamnionic twins (MCDA). Methods: The clinical data of 77 MCDA patients with structural malformations diagnosed by ultrasound were retrospectively reviewed from January 2012 to May 2017. The distribution of structural malformations, prenatal chromosomal karyotyping and pregnancy outcomes were analyzed. Results: (1)Among the 77 MCDA patients with structural malformations, the single malformation accounted for 79%(61/77), the multiple malformations accounted for 21%(16/77). And there were a total of 94 types of malformations, the top three malformations were neurological malformations (32%, 30/94), cardiovascular malformations (29%, 27/94) and twin reversed arterial perfusion sequence (TRAPS;10%,9/94).(2)Among the 77 patients with structural malformation, 64 cases (83%, 64/77) were examined for fetal chromosomes, of whom 14 cases (22%,14/64) were examined for fetal chromosomes of both twins, with 1 case (1/14) of discordant fetal chromosome. (3)Among the 77 patients, 4 cases (5%, 4/77) with severe fetal malformations terminated pregnancy. Totally 29 cases (38%,29/77) with severe malformations were treated with selective fetal reduction, among whom 7 cases (24%, 7/29) experienced unexplained fetal death within 24 hours after the operation; 2 cases (7%, 2/29) happened inevitable abortion, and 2 cases (7%, 2/29) underwent unexplained fetal death during the late pregnancy. Of the remaining 44 patients (57%,44/77) with expectant treatment, 13 cases (30%,13/44) occurred twin transfusion syndrome (Ⅱ-Ⅳ), and were treated with fetoscopic laser occlusion. Eight patients had 2 survival twins, 4 patients delivered 1 survival twin, and 1 patient had dead twins. Conclusions: The most common malformations in MCDA twins are the nervous malformations, cardiovascular malformations and TRAPS. The chromosome karyotype of MCDA twins with structural malformations are sometimes discordant, and separate samling of the twins is suggested for prenatal diagnosis. Selective fetal reduction could be given to severe structural malformation in MCDA patients safely and effectively. For non-severe structural malformation in MCDA patients with twin transfusion syndrome, fetoscopic laser occlusion is safe and effective.


Assuntos
Transtornos Cromossômicos/genética , Anormalidades Congênitas/genética , Doenças em Gêmeos/genética , Transfusão Feto-Fetal , Gravidez de Gêmeos , Gêmeos Monozigóticos/genética , Gêmeos/genética , Transtornos Cromossômicos/diagnóstico , Doenças em Gêmeos/diagnóstico , Feminino , Fetoscopia , Humanos , Cariotipagem , Gravidez , Gravidez de Gêmeos/genética , Gravidez de Gêmeos/fisiologia , Gravidez de Gêmeos/estatística & dados numéricos , Diagnóstico Pré-Natal , Estudos Retrospectivos , Ultrassonografia Pré-Natal
7.
Actas esp. psiquiatr ; 46(5): 192-199, sept.-oct. 2018. tab
Artigo em Espanhol | IBECS | ID: ibc-174687

RESUMO

Introducción. La incidencia y heredabilidad de los trastornos de la conducta alimentaria (TCA) se incrementa durante la pubertad. El objetivo de la presente investigación fue evaluar los cambios en las influencias genéticas ambientales sobre un amplio espectro de actitudes y conductas alimentarias anómalas durante la pubertad. Metodología. participaron 160 parejas de gemelas adolescentes, que se categorizaron en dos grupos en función del estado de menarquia (pre y pos). Medidas de TCA: Las actitudes y conductas alimentarias anómalas fueron evaluadas mediante el ChEAT (Children's Eating Attitudes Test) y cuatro subescalas del EDI (Eating Disorders Inventory); Impulso a la delgadez, Insatisfacción corporal, Ineficacia y Perfeccionismo. Las correlaciones intrapareja en gemelas MZ (monozigotas) y DZ (dizigotas) se calcularon por separado en los grupos de premenarquia y posmenarquia para cada medida de TCA. Resultados. Cuarenta y ocho gemelas premenarquia (30 MZ y 18 DZ) y 110 gemelas posmenarquia (66 MZ y 44 DZ). Las correlaciones sugirieron que no hay una influencia genética en la puntuación total del ChEAT en las niñas en estado premenarquia, mientras que en las niñas posmenarquia el porcentaje de la varianza para las influencias genéticas es elevado. En relación a las subescalas del EDI, únicamente la variable "Ineficacia" mostró una moderada heredabilidad en las niñas en estadio premenarquia, mientras que las cuatro actitudes alimentarias mostraron una moderada heredabilidad en el grupo de niñas posmenarquia. Conclusiones. Nuestro abordaje revela cambios significativos relacionados con la menarquia en las contribuciones de las influencias genéticas y ambientales sobre las conductas y actitudes alimentarias anómalas. Los clínicos deberían centrar su atención en las niñas adolescentes con alto riesgo de desarrollar TCA especialmente durante el periodo crítico de la menarquia


Background. Eating disorders' incidence and heritability significantly increase during puberty. The goal of this research is to evaluate changes during puberty which could have genetic and environmental influences on a broad spectrum of disordered eating attitudes and behaviors. Methods. Participants were 158 pairs of adolescent female twins, categorized in two groups according to menarche stage (pre or post). ED measures: Disordered eating attitudes and behaviors were assessed by means of the Children's Eating Attitudes Test and four sub-scales of the Eating Disorders Inventory: Drive for thinness, Body dissatisfaction, Ineffectiveness, and Perfectionism. Intra-class correlations in monozygotic (MZ) and dizygotic (DZ) twins were calculated separately in premenarche and premenarche group for each ED subscale Results. 48 premenarche twins (30 MZ twins and 18 DZ twins) and 110 premenarche twins (66 MZ and 44 DZ twins) were included. The intra-class correlations suggested no genetic influence on the total ChEAT score of participants at the premenarche stage. For the premenarche participants, however, sources of variance suggested a very high heritability. Regarding the EDI sub-scales, only the trait "Ineffectiveness" exhibited a moderate heritability among premenarche subjects, while all the four eating sub-scales showed moderate heritability estimates in the premenarche stage group. Conclusions. Our findings reveal that there are significant differences in genetic and environmental effects on eating attitudes and behaviors depending on being in a premenarche or premenarche stage. Therefore, clinicians should pay attention to female adolescents at high risk of developing ED, especially during the critical period of menarche


Assuntos
Humanos , Feminino , Adolescente , Transtornos da Alimentação e da Ingestão de Alimentos/epidemiologia , Menarca/fisiologia , Puberdade/genética , Nutrição do Adolescente , Fenômenos Fisiológicos da Nutrição do Adolescente/genética , Doenças em Gêmeos/genética , Gêmeos/genética , Transtornos da Alimentação e da Ingestão de Alimentos/psicologia , Menarca/psicologia , Transtornos da Alimentação e da Ingestão de Alimentos/genética , Índice de Massa Corporal , Puberdade/psicologia
8.
J Craniomaxillofac Surg ; 46(5): 802-807, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29551253

RESUMO

Hemifacial microsomia (HFM) is the second most common congenital craniofacial malformation. Although many sporadic and familial cases have been studied to explore the etiology and pathogenesis of HFM, no common understanding has been reached. We aimed to further probe into the etiology of HFM through studying monozygotic twins. Here, we report two cases of pairs of monozygotic twins discordant for HFM, and performed whole-exome sequencing (WES) and bioinformatics analysis to help determine the underlying molecular mechanisms. We identified 93 and 83, and 101 and 104 genes containing rare germline mutations in the twins of the two pairs, respectively. No positive gene candidates were found among the samples, and none of the analyses results revealed a clear intersection with previously reported gene candidates. The pathogenesis of HFM twin pairs does not appear to be related to single nucleotide variants or small insertions/deletions. Thus, HFM may be caused by structure variations, epigenetic alterations, and/or instability of short repeat sequences, which requires further investigation in a larger cohort with sequencing technology for verification.


Assuntos
Doenças em Gêmeos/genética , Síndrome de Goldenhar/genética , Gêmeos Monozigóticos/genética , Sequenciamento Completo do Exoma , Adolescente , Criança , Feminino , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética
9.
Brain Dev ; 40(7): 596-600, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29502866

RESUMO

We report a case of 14-month-old male monozygotic twins showing early-onset intractable epilepsy, delayed psychomotor development, hypotonia, opisthotonus, and dysmorphism. They presented with refractory partial and secondary generalized tonic-clonic or myoclonic seizures since age of 6 months. Electroencephalograms mainly revealed fast activity in left occipital region and generalized high amplitude polyspikes and wave. Brain MRI was normal. A de novo germline hemizygous mutation, C.110 T > C (p.37 M > T), in exon 2 of PIGA was confirmed, which indicated that a novel germline mutation in PIGA leads to early-onset epileptic encephalopathies.


Assuntos
Doenças em Gêmeos/genética , Epilepsia Resistente a Medicamentos/genética , Mutação em Linhagem Germinativa , Proteínas de Membrana/genética , Gêmeos Monozigóticos/genética , Epilepsia Resistente a Medicamentos/patologia , Epilepsia Resistente a Medicamentos/terapia , Face/anormalidades , Humanos , Lactente , Masculino
10.
J Affect Disord ; 232: 212-218, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29499503

RESUMO

BACKGROUND: Abnormalities in affective cognition are putative endophenotypes for bipolar and unipolar disorders but it is unclear whether some abnormalities are disorder-specific. We therefore investigated affective cognition in monozygotic twins at familial risk of bipolar disorder relative to those at risk of unipolar disorder and to low-risk twins. METHODS: Seventy monozygotic twins with a co-twin history of bipolar disorder (n = 11), of unipolar disorder (n = 38) or without co-twin history of affective disorder (n = 21) were included. Variables of interest were recognition of and vigilance to emotional faces, emotional reactivity and -regulation in social scenarios and non-affective cognition. RESULTS: Twins at familial risk of bipolar disorder showed increased recognition of low to moderate intensity of happy facial expressions relative to both unipolar disorder high-risk twins and low-risk twins. Bipolar disorder high-risk twins also displayed supraliminal attentional avoidance of happy faces compared with unipolar disorder high-risk twins and greater emotional reactivity in positive and neutral social scenarios and less reactivity in negative social scenarios than low-risk twins. In contrast with our hypothesis, there was no negative bias in unipolar disorder high-risk twins. There were no differences between the groups in demographic characteristics or non-affective cognition. LIMITATIONS: The modest sample size limited the statistical power of the study. CONCLUSIONS: Increased sensitivity and reactivity to positive social stimuli may be a neurocognitive endophenotype that is specific for bipolar disorder. If replicated in larger samples, this 'positive endophenotype' could potentially aid future diagnostic differentiation between unipolar and bipolar disorder.


Assuntos
Sintomas Afetivos/fisiopatologia , Transtorno Bipolar/fisiopatologia , Transtorno Depressivo/fisiopatologia , Doenças em Gêmeos/fisiopatologia , Endofenótipos , Gêmeos Monozigóticos/genética , Adulto , Sintomas Afetivos/genética , Atenção , Transtorno Bipolar/genética , Cognição , Transtorno Depressivo/genética , Doenças em Gêmeos/genética , Emoções/fisiologia , Expressão Facial , Feminino , Humanos , Masculino , Risco
11.
Croat Med J ; 59(1): 20-24, 2018 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-29498494

RESUMO

We describe a case of twins with sporadic Gorlin syndrome. Both twins had common Gorlin syndrome features including calcification of the falx cerebri, multiple jaw keratocysts, and multiple basal cell carcinomas, but with different expressivity. One brother also had benign testicular mesothelioma. We propose this tumor type as a possible new feature of Gorlin syndrome. Gorlin syndrome is a rare autosomal dominant disorder characterized by both developmental abnormalities and cancer predisposition, with variable expression of various developmental abnormalities and different types of tumors. The syndrome is primarily caused by mutations in the Patched 1 (PTCH1) gene, although rare mutations of Patched 2 (PTCH2) or Suppressor of Fused (SUFU) genes have also been found. Neither founder mutations nor hot spot locations have been described for PTCH1 in Gorlin syndrome patients. Although de novo mutations of the PTCH1 gene occur in almost 50% of Gorlin syndrome cases, there are a few recurrent mutations. Our twin patients were carriers of a de novo mutation in the PTCH1 gene, c.3364_3365delAT (p.Met1122ValfsX22). This is, to our knowledge, the first Gorlin syndrome-causing mutation that has been reported four independent times in distant geographical locations. Therefore, we propose the location of the described mutation as a potential hot spot for mutations in PTCH1.


Assuntos
Síndrome do Nevo Basocelular/genética , Doenças em Gêmeos/genética , Mutação , Receptor Patched-1/genética , Neoplasias Cutâneas/genética , Gêmeos Monozigóticos/genética , Adulto , Sequência de Bases , Ligação Genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único
12.
Behav Genet ; 48(2): 109-124, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29427143

RESUMO

We investigated the etiological role of genetic and environmental influences for two milestones of tobacco and alcohol use: age of initiation, and speed of progression to dependence (latency). Study participants included 1352 monozygotic and 1422 dizygotic twins (mean age at assessment = 24.31). Earlier ages of initiation significantly increased the likelihood of developing dependence, but were associated with longer dependence latencies for tobacco and alcohol. Latencies to dependence were heritable traits for tobacco (a2 = 0.63) and alcohol (a2 = 0.64). Genetic influences contributing to early age of initiation were associated with faster latencies to dependence but sometimes were counteracted by environmental factors, the extent to which depended on substance and, sometimes, sex. Our findings may have important implications for public policy and add to the literature by characterizing the genetic and environmental contributions to the speed of progression to tobacco and alcohol dependence.


Assuntos
Alcoolismo/genética , Tabagismo/genética , Adolescente , Adulto , Fatores Etários , Consumo de Bebidas Alcoólicas/genética , Doenças em Gêmeos/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Fatores de Risco , Fumar/genética , Transtornos Relacionados ao Uso de Substâncias/genética , Tabaco , Gêmeos/genética , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Adulto Jovem
13.
Gene ; 658: 96-104, 2018 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-29477871

RESUMO

Hirschsprung's disease (HSCR) is a complex disorder with multiple pathogenic gene mutations. Protocadherin alpha 9 (PCDHA9) was identified as a potential candidate gene for HSCR by whole-exome sequencing in a Chinese family. Sanger sequencing in 298 HSCR cases revealed two sporadic Chinese patients with a novel missence PCDHΑ9 mutation (NM_031857; c.1280C > T[p.Ala427Val]) and one sporadic Chinese patient with another novel missence PCDHΑ9 mutation (c.1425C > G[p.Phe475Leu]).The silico predictions and 3D modeling suggest the deleterious effect of identified mutations on protein function. Immunohistochemistry analysis showed PCDHΑ9 was predominantly expressed in the myenteric plexus of human colon tissues. For mouse embryos, PCDHΑ9 was expressed in the stomach but rarely seen in the intestine during E10.5-12.5, then obviously expressed in the intestinal mucosa at E13.5 and extensively expressed in intestinal muscularis and mucosa at E14.5. Moreover, the down-regulation of PCDHΑ9 in the SH-SY5Y cell line promoted the proliferation and migration rate but inhibited the apoptotic rate. In summary, PCDHΑ9 is potentially related to HSCR and the clustered protocadherins (Pcdhs) may involve in the enteric nervous system (ENS) ontogeny.


Assuntos
Caderinas/genética , Doença de Hirschsprung/genética , Mutação de Sentido Incorreto , Substituição de Aminoácidos , Animais , Células Cultivadas , Análise Mutacional de DNA , Doenças em Gêmeos/genética , Embrião de Mamíferos , Sistema Nervoso Entérico/embriologia , Sistema Nervoso Entérico/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Linhagem , Gravidez , Irmãos , Gêmeos Monozigóticos
14.
Twin Res Hum Genet ; 21(1): 1-11, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29307321

RESUMO

Hundreds of penetrant risk loci have been identified across different neurodevelopmental disorders (NDDs), and these often involve rare (<1% frequency) copy number variations (CNVs), which can involve one or more genes. Monozygotic (MZ) twin pairs are long thought to share 100% of their genomic information. However, genetic differences in the form of postzygotic somatic variants have been reported recently both in typically developing (TD) and in clinically discordant MZ pairs. We sought to investigate the contribution of rare CNVs in 100 twin pairs enriched for NDD phenotypes with a particular focus on postzygotic CNVs in MZ pairs discordant for autism spectrum disorder (ASD) using the Illumina Infinium PsychArray. In our sample, no postzygotic de novo CNVs were found in 55 MZ twin pairs, including the 13 pairs discordant for ASD. We did detect a higher rate of CNVs overlapping genes involved in disorders of the nervous system, such as a rare deletion affecting HNRNPU, in MZ pairs discordant and concordant for ASD in comparison with TD pairs (p = .02). Our results are in concordance with earlier findings that postzygotic de novo CNV events are typically rare in genomic DNA derived from saliva or blood, and suggests that the discordance of NDDs in our sample of twins is not explained by discordant CNVs. Still, studies investigating postzygotic variation in MZ discordant twins using DNA from different tissues and single cells and higher resolution genomics are needed in the future.


Assuntos
Variações do Número de Cópias de DNA , Doenças em Gêmeos/genética , Transtornos do Neurodesenvolvimento/genética , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Adolescente , Adulto , Transtorno do Espectro Autista/genética , Criança , Feminino , Humanos , Masculino , Suécia , Adulto Jovem
15.
Twin Res Hum Genet ; 21(1): 24-32, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29369040

RESUMO

Until now, data have not been available to elucidate the genetic and environmental sources of comorbidity between all 10 DSM-IV personality disorders (PDs) and cocaine use. Our aim was to determine which PD traits are linked phenotypically and genetically to cocaine use. Cross-sectional data were obtained in a face-to-face interview between 1999 and 2004. Subjects were 1,419 twins (µage = 28.2 years, range = 19-36) from the Norwegian Institute of Public Health Twin Panel, with complete lifetime cocaine use and criteria for all 10 DSM-IV PDs. Stepwise multiple and Least Absolute Shrinkage and Selection Operator (LASSO) regressions were used to identify PDs related to cocaine use. Twin models were fitted to estimate genetic and environmental associations between the PD traits and cocaine use. In the multiple regression, antisocial (OR = 4.24, 95% CI [2.66, 6.86]) and borderline (OR = 2.19, 95% CI [1.35, 3.57]) PD traits were significant predictors of cocaine use. In the LASSO regression, antisocial, borderline, and histrionic were significant predictors of cocaine use. Antisocial and borderline PD traits each explained 72% and 25% of the total genetic risks in cocaine use, respectively. Genetic risks in histrionic PD were not significantly related to cocaine use. Importantly, after removing criteria referencing substance use, antisocial PD explained 65% of the total genetic variance in cocaine use, whereas borderline explained only 4%. Among PD traits, antisocial is the strongest correlate of cocaine use, for which the association is driven largely by common genetic risks.


Assuntos
Transtornos Relacionados ao Uso de Cocaína/genética , Transtornos Relacionados ao Uso de Cocaína/psicologia , Transtornos da Personalidade/genética , Adulto , Transtorno da Personalidade Antissocial/genética , Estudos Transversais , Doenças em Gêmeos/genética , Feminino , Interação Gene-Ambiente , Humanos , Masculino , Análise Multivariada , Noruega , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Adulto Jovem
16.
BMC Public Health ; 18(1): 145, 2018 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-29343229

RESUMO

BACKGROUND: The disease burden related to mental disorders and metabolic syndrome is growing in low-and middle-income countries (LMIC). The Colombo Twin and Singleton Study (COTASS) is a population-based sample of twins and singletons in Colombo, Sri Lanka. Here we present prevalence estimates for metabolic syndrome (metS) and mental disorders from a follow-up (COTASS-2) of the original study (COTASS-1), which was a mental health survey. METHODS: In COTASS-2, participants completed structured interviews, anthropometric measures and provided fasting blood and urine samples. Depressive disorder, depressive symptoms, anxiety symptoms, post-traumatic stress disorder (PTSD) and hazardous alcohol use were ascertained with structured psychiatric screens (Composite International Diagnostic Interview (CIDI), Beck Depression Inventory (BDI-II), Generalised Anxiety Disorder Questionnaire (GAD-7), PTSD Checklist - Civilian Version (PCL-C), and Alcohol Use Disorders Identification Test (AUDIT)). We defined metS according to the International Diabetes Federation (IDF) criteria and the revised National Cholesterol Education Programme Adult Treatment Panel (NCEP ATP III) criteria. We estimated the prevalence of psychiatric disorders and metS and metS components, and associations with gender, education and age. RESULTS: Two thousand nine hundred thirty-four twins and 1035 singletons were followed up from COTASS-1 (83.4 and 61.8% participation rate, respectively). Prevalence estimates for depressive disorder (CIDI), depressive symptoms (BDI ≥ 16), anxiety symptoms (GAD-7 ≥ 10) and PTSD (PCL-C DSM criteria) were 3.8, 5.9, 3.6, and 4.5% respectively for twins and 3.9, 9.8, 5.1 and 5.4% for singletons. 28.1 and 30.9% of male twins and singletons respectively reported hazardous alcohol use. Approximately one third met the metS criteria (IDF: 27.4% twins, 44.6% singletons; NCEP ATP III: 30.6% twins, 48.6% singletons). The most prevalent components were central obesity (59.2% twins, 71.2% singletons) and raised fasting blood glucose or diabetes (38.2% twins, 56.7% singletons). CONCLUSION: MetS was highly prevalent in twins, and especially high in singletons, whereas the prevalence of mental disorders was low, but consistent with local estimates. The high levels of raised fasting plasma glucose and central obesity were particularly concerning, and warrant national diabetes prevention programmes.


Assuntos
Doenças em Gêmeos/epidemiologia , Doenças em Gêmeos/genética , Transtornos Mentais/epidemiologia , Transtornos Mentais/genética , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Interação Gene-Ambiente , Inquéritos Epidemiológicos , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Prevalência , Fatores Socioeconômicos , Sri Lanka/epidemiologia , Gêmeos/genética , Adulto Jovem
17.
Depress Anxiety ; 35(2): 132-139, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29283198

RESUMO

BACKGROUND: To examine shared genetic and environmental risk factors across PTSD symptoms and resilience. METHODS: Classical twin study of 2010-2012 survey data conducted among 3,318 male twin pairs in the Vietnam Era Twin Registry. Analyses included: (a) estimates of genetic and environmental influences on PTSD symptom severity (as measured by the PTSD Checklist) and resilience (assessed with the Connor-Davidson Resilience Scale-10); (b) development of a latent model of traumatic stress, spanning both PTSD and resilience; and (c) estimates of genetic and environmental influences on this spectrum. RESULTS: The heritability of PTSD was 49% and of resilience was 25%. PTSD and resilience were correlated at r = -.59, and 59% of this correlation was attributable to a single genetic factor, whereas the remainder was due to a single non-shared environment factor. Resilience was also influenced by common and unique environmental factors not shared with PTSD, but there was no genetic factor specific to resilience. Confirmatory factor analysis supported the Development of a revised phenotype reflecting the broader dimension of traumatic stress, with biometric models suggesting increased heritability (66%) of this spectrum compared to PTSD or resilience individually. CONCLUSIONS: Genetic factors contribute to a single spectrum of traumatic stress reflecting resilience at one end and high symptom severity at the other. This carries implications for phenotype refinement in the search for molecular genetic markers of trauma-related psychopathology. Rather than focusing only on genetic risk for PTSD, molecular genetics research may benefit from evaluation of the broader spectrum of traumatic stress.


Assuntos
Suscetibilidade a Doenças , Doenças em Gêmeos , Sistema de Registros , Resiliência Psicológica , Transtornos de Estresse Pós-Traumáticos , Idoso , Doenças em Gêmeos/epidemiologia , Doenças em Gêmeos/etiologia , Doenças em Gêmeos/genética , Doenças em Gêmeos/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Transtornos de Estresse Pós-Traumáticos/etiologia , Transtornos de Estresse Pós-Traumáticos/genética , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Veteranos/estatística & dados numéricos
18.
Behav Genet ; 48(1): 22-33, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29150722

RESUMO

Understanding the factors that contribute to behavioral traits is a complex task, and partitioning variance into latent genetic and environmental components is a useful beginning, but it should not also be the end. Many constructs are influenced by their contextual milieu, and accounting for background effects (such as gene-environment correlation) is necessary to avoid bias. This study introduces a method for examining the interplay between traits, in a longitudinal design using differential items in sibling pairs. The model is validated via simulation and power analysis, and we conclude with an application to paternal praise and ADHD symptoms in a twin sample. The model can help identify what type of genetic and environmental interplay may contribute to the dynamic relationship between traits using a cross-lagged panel framework. Overall, it presents a way to estimate and explicate the developmental interplay between a set of traits, free from many common sources of bias.


Assuntos
Controle Comportamental/métodos , Herança Multifatorial/genética , Adolescente , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/genética , Criança , Simulação por Computador , Doenças em Gêmeos/genética , Feminino , Interação Gene-Ambiente , Humanos , Masculino , Poder Familiar/psicologia , Comportamento Paterno/psicologia , Fenótipo , Reprodutibilidade dos Testes , Projetos de Pesquisa/estatística & dados numéricos , Irmãos/psicologia , Gêmeos Monozigóticos/genética , Gêmeos Monozigóticos/psicologia
19.
Graefes Arch Clin Exp Ophthalmol ; 256(2): 333-340, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29242987

RESUMO

PURPOSE: To establish the prevalence and heritability of cilioretinal arteries (CRAs), tilted discs (TDs) and situs inversus (SI). METHODS: Fundus photos from the Twins UK Adult Twin registry twin database were analyzed: 1812 individuals, 526 complete monozygotic (MZ) twin pairs and 336 complete dizygotic (DZ) pairs. Images were assessed non-stereoscopically on a computer screen by the same ophthalmologist for presence of CRAs, TDs or SI. Prevalence figures, probandwise concordances and heritabilities were calculated. RESULTS: Prevalence of a CRA in subjects' right eyes was 28.6% (26.5-30.8). Prevalence of subjects with a CRA in at least one eye was 45.0% (42.6-47.5), with a TD in at least one eye was 1.2% (0.8-1.9), and with SI at least one eye was 0.5% (0.3-1.0). There was no association between birth weight and presence of CRA. Concordance for CRA in at least one eye (MZ twins) was 60% (95% CI 55-64), and (DZ) was 45% (95% CI 39-51). Heritability for CRAs in at least one eye was 49.4% (95% CI 38.1-59.7) and for both eyes was 32.9% (95% CI 10.4-53.3). We were unable to calculate meaningful heritabilities or concordances for TDs and situs SI, due to insufficient numbers. CONCLUSIONS: The presence of CRAs appears to be moderately heritable, with greater variance explained by individual environmental factors or even stochastic events. They were not associated with low birth weight. Future genetic research and studies of birth/lifecourse cohorts may offer further insights into the etiology of congenital papillovascular abnormalities.


Assuntos
Anormalidades Múltiplas , Artérias Ciliares/patologia , Doenças em Gêmeos/genética , Disco Óptico/anormalidades , Doenças do Nervo Óptico/genética , Artéria Retiniana/patologia , Situs Inversus/genética , Doenças em Gêmeos/diagnóstico , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Doenças do Nervo Óptico/diagnóstico , Sistema de Registros , Situs Inversus/diagnóstico , Gêmeos Monozigóticos
20.
Semin Arthritis Rheum ; 47(4): 538-544, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28755788

RESUMO

OBJECTIVE: To determine the concordance of systemic lupus erythematosus (SLE) and co-aggregating autoimmune diseases among Danish twins. METHODS: SLE-affected twins were ascertained by record linkage between the National Patient Register (NPR) and the Danish Twin Registry (DTR). Registered SLE codes were validated through medical chart review and information from the treating physicians. Twin pairs with at least one chart-validated SLE proband were invited to participate in a personal interview and clinical validation of the SLE diagnoses. RESULTS: Twenty-two twins fulfilled the ACR criteria for SLE. The age- and sex-adjusted point SLE prevalence in the Danish twin cohort was 30.3 per 100,000 persons (95% CI: 19.2-46.5). Among seven monozygotic (MZ), eight same-sex dizygotic (DZss) and five opposite-sex dizygotic (DZos) twin pairs, one MZ and one DZss were concordant for SLE. This corresponded to probandwise concordance rates of 25.0% (95% CI: 7.15-59.1) and 7.7% (95% CI: 1.37-33.3), and pairwise concordance rates of 14.3% (95% CI: 2.57-51.3) and 7.7% (95% CI: 1.37-33.3) among MZ and DZ twins, respectively. An SLE diagnosis was clinically validated in 17 twins from 15 twin pairs. Another four co-twins had other autoimmune disease, corresponding to a probandwise concordance of any autoimmune disease of 50.0% in MZ (95% CI: 21.5-78.5) and 23.1% in DZ twins (95% CI: 8.18-50.3). CONCLUSION: Population-based Danish data suggest that SLE twin concordance is lower than previously reported, but still point to the importance of both genetic and environmental factors, and indicate a substantial co-aggregation of other autoimmune diseases in SLE twins.


Assuntos
Doenças Autoimunes/epidemiologia , Doenças em Gêmeos/epidemiologia , Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/epidemiologia , Adulto , Doenças Autoimunes/genética , Comorbidade , Dinamarca/epidemiologia , Doenças em Gêmeos/genética , Feminino , Humanos , Lúpus Eritematoso Sistêmico/genética , Masculino , Pessoa de Meia-Idade , Prevalência , Sistema de Registros
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