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1.
Twin Res Hum Genet ; : 1-4, 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31796140

RESUMO

Here we provide an update of the 2013 report on the Nigerian Twin and Sibling Registry (NTSR). The major aim of the NTSR is to understand genetic and environmental influences and their interplay in psychological and mental health development in Nigerian children and adolescents. Africans have the highest twin birth rates among all human populations, and Nigeria is the most populous country in Africa. Due to its combination of large population and high twin birth rates, Nigeria has one of the largest twin populations in the world. In this article, we provide current updates on the NTSR samples recruited, recruitment procedures, zygosity assessment and findings emerging from the NTSR.

2.
Twin Res Hum Genet ; : 1-14, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31666148

RESUMO

The Netherlands Twin Register (NTR) is a national register in which twins, multiples and their parents, siblings, spouses and other family members participate. Here we describe the NTR resources that were created from more than 30 years of data collections; the development and maintenance of the newly developed database systems, and the possibilities these resources create for future research. Since the early 1980s, the NTR has enrolled around 120,000 twins and a roughly equal number of their relatives. The majority of twin families have participated in survey studies, and subsamples took part in biomaterial collection (e.g., DNA) and dedicated projects, for example, for neuropsychological, biomarker and behavioral traits. The recruitment into the NTR is all inclusive without any restrictions on enrollment. These resources - the longitudinal phenotyping, the extended pedigree structures and the multigeneration genotyping - allow for future twin-family research that will contribute to gene discovery, causality modeling, and studies of genetic and cultural inheritance.

3.
Nutrients ; 11(11)2019 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-31744183

RESUMO

Breastfeeding has long-term benefits for children that may be mediated via the epigenome. This pathway has been hypothesized, but the number of empirical studies in humans is small and mostly done by using peripheral blood as the DNA source. We performed an epigenome-wide association study (EWAS) in buccal cells collected around age nine (mean = 9.5) from 1006 twins recruited by the Netherlands Twin Register (NTR). An age-stratified analysis examined if effects attenuate with age (median split at 10 years; n<10 = 517, mean age = 7.9; n>10 = 489, mean age = 11.2). We performed replication analyses in two independent cohorts from the NTR (buccal cells) and the Avon Longitudinal Study of Parents and Children (ALSPAC) (peripheral blood), and we tested loci previously associated with breastfeeding in epigenetic studies. Genome-wide DNA methylation was assessed with the Illumina Infinium MethylationEPIC BeadChip (Illumina, San Diego, CA, USA) in the NTR and with the HumanMethylation450 Bead Chip in the ALSPAC. The duration of breastfeeding was dichotomized ('never' vs. 'ever'). In the total sample, no robustly associated epigenome-wide significant CpGs were identified (α = 6.34 × 10-8). In the sub-group of children younger than 10 years, four significant CpGs were associated with breastfeeding after adjusting for child and maternal characteristics. In children older than 10 years, methylation differences at these CpGs were smaller and non-significant. The findings did not replicate in the NTR sample (n = 98; mean age = 7.5 years), and no nearby sites were associated with breastfeeding in the ALSPAC study (n = 938; mean age = 7.4). Of the CpG sites previously reported in the literature, three were associated with breastfeeding in children younger than 10 years, thus showing that these CpGs are associated with breastfeeding in buccal and blood cells. Our study is the first to show that breastfeeding is associated with epigenetic variation in buccal cells in children. Further studies are needed to investigate if methylation differences at these loci are caused by breastfeeding or by other unmeasured confounders, as well as what mechanism drives changes in associations with age.

4.
Twin Res Hum Genet ; : 1-5, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31608846

RESUMO

The aim of the Avera Twin Register (ATR) is to establish a prospective longitudinal repository of twins, multiples, siblings and family members' biological samples to study environmental and genetic influences on health and disease. Also, it is our intention to contribute to international genome-wide association study (GWAS) twin consortia when appropriate sample size is achieved within the ATR. The ATR is young compared with existing registers and continues to collect a longitudinal repository of biological specimens, survey data and health information. Data and biological specimens were originally collected via face-to-face appointments or the postal department and consisted of paper-informed consents and questionnaires. Enrollment of the ATR began on May 18, 2016 and is located in Sioux Falls, South Dakota, a rural and frontier area in the Central United States with a regional population of approximately 880,000. The original target area for the ATR was South Dakota and the four surrounding states: Minnesota, Iowa, North Dakota and Nebraska. The ATR has found a need to expand that area based on twin and multiple siblings who live in various areas surrounding these states. A description of the state of the ATR today and its transition to online data collection and informed consent will be presented. The ATR collects longitudinal data on lifestyle, including diet and activity levels, aging, plus complex traits and diseases. All twins and multiples participating in the ATR are genotyped on the Illumina Global Screening Array and receive zygosity results.

5.
BMC Microbiol ; 19(1): 230, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31640566

RESUMO

BACKGROUND: The gut microbiota composition is known to be influenced by a myriad of factors including the host genetic profile and a number of environmental influences. Here, we focus on the environmental influence of cohabitation on the gut microbiota as well as whether these environmentally influenced microorganisms are associated with cardiometabolic and inflammatory burden. We perform this by investigating the gut microbiota composition of various groups of related individuals including cohabitating monozygotic (MZ) twin pairs, non-cohabitating MZ twin pairs and spouse pairs. RESULTS: A stronger correlation between alpha diversity was found in cohabitating MZ twins (45 pairs, r = 0.64, p = 2.21 × 10- 06) than in non-cohabitating MZ twin pairs (121 pairs, r = 0.42, p = 1.35 × 10- 06). Although the correlation of alpha diversity did not attain significance between spouse pairs (42 pairs, r = 0.23, p = 0.15), the correlation was still higher than those in the 209 unrelated pairs (r = - 0.015, p = 0.832). Bray-Curtis (BC) dissimilarity metrics showed cohabitating MZ twin pairs had the most similar gut microbiota communities which were more similar than the BC values of non-cohabitating MZ twins (empirical p-value = 0.0103), cohabitating spouses (empirical p-value = 0.0194), and pairs of unrelated non-cohabitating individuals (empirical p-value< 0.00001). There was also a significant difference between the BC measures from the spouse pairs and those from the unrelated non-cohabitating individuals (empirical p-value< 0.00001). Intraclass correlation coefficients were calculated between the various groups of interest and the results indicate the presence of OTUs with an environmental influence and one OTU that appeared to demonstrate genetic influences. One of the OTUs (Otu0190) was observed to have a significant association with both the cardiometabolic and inflammatory burden scores (p's < 0.05). CONCLUSIONS: Through the comparison of the microbiota contents of MZ twins with varying cohabitation status and spousal pairs, we showed evidence of environmentally influenced OTUs, one of which had a significant association with cardiometabolic and inflammatory burden scores.

6.
Twin Res Hum Genet ; 22(4): 210-219, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31379313

RESUMO

Twin registries often take part in large collaborative projects and are major contributors to genome-wide association (GWA) meta-analysis studies. In this article, we describe genotyping of twin-family populations from Australia, the Midwestern USA (Avera Twin Register), the Netherlands (Netherlands Twin Register), as well as a sample of mothers of twins from Nigeria to assess the extent, if any, of genetic differences between them. Genotyping in all cohorts was done using a custom-designed Illumina Global Screening Array (GSA), optimized to improve imputation quality for population-specific GWA studies. We investigated the degree of genetic similarity between the populations using several measures of population variation with genotype data generated from the GSA. Visualization of principal component analysis (PCA) revealed that the Australian, Dutch and Midwestern American populations exhibit negligible interpopulation stratification when compared to each other, to a reference European population and to globally distant populations. Estimations of fixation indices (FST values) between the Australian, Midwestern American and Netherlands populations suggest minimal genetic differentiation compared to the estimates between each population and a genetically distinct cohort (i.e., samples from Nigeria genotyped on GSA). Thus, results from this study demonstrate that genotype data from the Australian, Dutch and Midwestern American twin-family populations can be reasonably combined for joint-genetic analysis.

7.
Blood ; 134(15): 1227-1237, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31350265

RESUMO

Children with Down syndrome (DS) have a 20-fold increased risk of acute lymphoblastic leukemia (ALL) and distinct somatic features, including CRLF2 rearrangement in ∼50% of cases; however, the role of inherited genetic variation in DS-ALL susceptibility is unknown. We report the first genome-wide association study of DS-ALL, comprising a meta-analysis of 4 independent studies, with 542 DS-ALL cases and 1192 DS controls. We identified 4 susceptibility loci at genome-wide significance: rs58923657 near IKZF1 (odds ratio [OR], 2.02; Pmeta = 5.32 × 10-15), rs3731249 in CDKN2A (OR, 3.63; Pmeta = 3.91 × 10-10), rs7090445 in ARID5B (OR, 1.60; Pmeta = 8.44 × 10-9), and rs3781093 in GATA3 (OR, 1.73; Pmeta = 2.89 × 10-8). We performed DS-ALL vs non-DS ALL case-case analyses, comparing risk allele frequencies at these and other established susceptibility loci (BMI1, PIP4K2A, and CEBPE) and found significant association with DS status for CDKN2A (OR, 1.58; Pmeta = 4.1 × 10-4). This association was maintained in separate regression models, both adjusting for and stratifying on CRLF2 overexpression and other molecular subgroups, indicating an increased penetrance of CDKN2A risk alleles in children with DS. Finally, we investigated functional significance of the IKZF1 risk locus, and demonstrated mapping to a B-cell super-enhancer, and risk allele association with decreased enhancer activity and differential protein binding. IKZF1 knockdown resulted in significantly higher proliferation in DS than non-DS lymphoblastoid cell lines. Our findings demonstrate a higher penetrance of the CDKN2A risk locus in DS and serve as a basis for further biological insights into DS-ALL etiology.

8.
Birth Defects Res ; 111(13): 932-937, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31102501

RESUMO

BACKGROUND: Recent genome-wide association studies of hypospadias have implicated the role of genetic variants in or near the diacylglycerol kinase kappa (DGKK) gene. However, these variants are largely identified among samples of mild and moderate hypospadias cases. Therefore, we evaluated previously identified DGKK variants among second- and third-degree hypospadias cases and controls recruited in Arkansas, a state characterized by a high birth prevalence of hypospadias. METHODS: Second- and third-degree hypospadias non-Hispanic white cases (n = 36 and n = 9, respectively) and controls (n = 45) were recruited at Arkansas Children's Hospital. Preputial tissue was collected on cases and controls between 2013 and 2017. Cases and controls were genotyped using the Illumina Infinium Global Screening Array. We used logistic regression models to assess the association of genotyped and imputed genetic variants mapped to the DGKK region with second- and third-degree hypospadias. RESULTS: All families self-reported as non-Hispanic white and genetic principal component analyses did not demonstrate evidence of population stratification. Five DGKK variants previously reported as associated with hypospadias were identified in the genotype data. None of the variants were associated with second- or third-degree hypospadias (range of odds ratios = 0.7-0.9, all p > .05). CONCLUSIONS: In our analyses, genetic variation in DGKK does not play a role in the development of moderate and severe hypospadias. Our findings provide support to the etiologic heterogeneity of hypospadias by all classifications of severity.

9.
EBioMedicine ; 42: 296-303, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30905849

RESUMO

BACKGROUND: Genomic investigation of atypical adenomatous hyperplasia (AAH), the only known precursor lesion to lung adenocarcinomas (LUAD), presents challenges due to the low mutant cell fractions. This necessitates sensitive methods for detection of chromosomal aberrations to better study the role of critical alterations in early lung cancer pathogenesis and the progression from AAH to LUAD. METHODS: We applied a sensitive haplotype-based statistical technique to detect chromosomal alterations leading to allelic imbalance (AI) from genotype array profiling of 48 matched normal lung parenchyma, AAH and tumor tissues from 16 stage-I LUAD patients. To gain insights into shared developmental trajectories among tissues, we performed phylogenetic analyses and integrated our results with point mutation data, highlighting significantly-mutated driver genes in LUAD pathogenesis. FINDINGS: AI was detected in nine AAHs (56%). Six cases exhibited recurrent loss of 17p. AI and the enrichment of 17p events were predominantly identified in patients with smoking history. Among the nine AAH tissues with detected AI, seven exhibited evidence for shared chromosomal aberrations with matched LUAD specimens, including losses harboring tumor suppressors on 17p, 8p, 9p, 9q, 19p, and gains encompassing oncogenes on 8q, 12p and 1q. INTERPRETATION: Chromosomal aberrations, particularly 17p loss, appear to play critical roles early in AAH pathogenesis. Genomic instability in AAH, as well as truncal chromosomal aberrations shared with LUAD, provide evidence for mutation accumulation and are suggestive of a cancerized field contributing to the clonal selection and expansion of these premalignant lesions. FUND: Supported in part by Cancer Prevention and Research Institute of Texas (CPRIT) grant RP150079 (PS and HK), NIH grant R01HG005859 (PS) and The University of Texas MD Anderson Cancer Center Core Support Grant.


Assuntos
Transformação Celular Neoplásica/genética , Pulmão/metabolismo , Pulmão/patologia , Lesões Pré-Cancerosas/genética , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Desequilíbrio Alélico , Instabilidade Cromossômica , Progressão da Doença , Feminino , Heterogeneidade Genética , Estudo de Associação Genômica Ampla , Haplótipos , Humanos , Hiperplasia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Mutação , Estadiamento de Neoplasias , Filogenia , Polimorfismo de Nucleotídeo Único , Adulto Jovem
10.
Am J Respir Crit Care Med ; 200(6): 742-750, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-30896962

RESUMO

Rationale: Uninvolved normal-appearing airway epithelium has been shown to exhibit specific mutations characteristic of nearby non-small cell lung cancers (NSCLCs). Yet, its somatic mutational landscape in patients with early-stage NSCLC is unknown.Objectives: To comprehensively survey the somatic mutational architecture of the normal airway epithelium in patients with early-stage NSCLC.Methods: Multiregion normal airways, comprising tumor-adjacent small airways, tumor-distant large airways, nasal epithelium and uninvolved normal lung (collectively airway field), matched NSCLCs, and blood cells (n = 498) from 48 patients were interrogated for somatic single-nucleotide variants by deep-targeted DNA sequencing and for chromosomal allelic imbalance events by genome-wide genotype array profiling. Spatiotemporal relationships between the airway field and NSCLCs were assessed by phylogenetic analysis.Measurements and Main Results: Genomic airway field carcinogenesis was observed in 25 cases (52%). The airway field epithelium exhibited a total of 269 somatic mutations in most patients (n = 36) including key drivers that were shared with the NSCLCs. Allele frequencies of these acquired variants were overall higher in NSCLCs. Integrative analysis of single-nucleotide variants and allelic imbalance events revealed driver genes with shared "two-hit" alterations in the airway field (e.g., TP53, KRAS, KEAP1, STK11, and CDKN2A) and those with single hits progressing to two in the NSCLCs (e.g., PIK3CA and NOTCH1).Conclusions: Tumor-adjacent and tumor-distant normal-appearing airway epithelia exhibit somatic driver alterations that undergo selection-driven clonal expansion in NSCLC. These events offer spatiotemporal insights into the development of NSCLC and, thus, potential targets for early treatment.

11.
Eur J Hum Genet ; 27(6): 970-979, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30760885

RESUMO

The tendency to conceive spontaneous dizygotic (DZ) twins is a complex trait with important contributions from both environmental factors and genetic disposition. In earlier work, we identified the first two genes as maternal susceptibility loci for DZ twinning. The aim of this study was to identify genetic variants influencing multiple births and to genetically correlate the findings across a broad range of traits. We performed a genome-wide association study (GWAS) in 8962 participants with Caucasian ancestry from UK Biobank who reported being part of a multiple birth, and 409,591 singleton controls. We replicated the association between FSHB, SMAD3 and twinning in the gene-based (but not SNP-based) test, which had been established in previous genome-wide association analyses in mothers with dizygotic twin offspring. Additionally, we report a novel genetic variant associated with multiple birth, rs428022 at 15q23 (p = 2.84 × 10-8) close to two genes: PIAS1 and SKOR1. Finally, we identified meaningful genetic correlations between being part of a multiple birth and other phenotypes (anthropometric traits, health-related traits, and fertility-related measures). The outcomes of this study provide important new insights into the genetic aetiology of multiple births and fertility, and open up novel directions for fertility and reproduction research.

13.
J Mammary Gland Biol Neoplasia ; 23(4): 237-248, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30338425

RESUMO

Ductal carcinoma in situ (DCIS) is a non-obligate precursor to most types of invasive breast cancer (IBC). Although it is estimated only one third of untreated patients with DCIS will progress to IBC, standard of care for treatment is surgery and radiation. This therapeutic approach combined with a lack of reliable biomarker panels to predict DCIS progression is a major clinical problem. DCIS shares the same molecular subtypes as IBC including estrogen receptor (ER) and progesterone receptor (PR) positive luminal subtypes, which encompass the majority (60-70%) of DCIS. Compared to the established roles of ER and PR in luminal IBC, much less is known about the roles and mechanism of action of estrogen (E2) and progesterone (P4) and their cognate receptors in the development and progression of DCIS. This is an underexplored area of research due in part to a paucity of suitable experimental models of ER+/PR + DCIS. This review summarizes information from clinical and observational studies on steroid hormones as breast cancer risk factors and ER and PR as biomarkers in DCIS. Lastly, we discuss emerging experimental models of ER+/PR+ DCIS.

14.
Epigenetics Chromatin ; 11(1): 54, 2018 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-30253792

RESUMO

BACKGROUND: DNA methylation arrays are widely used in epigenome-wide association studies and methylation quantitative trait locus (mQTL) studies. Here, we performed the first genome-wide analysis of monozygotic (MZ) twin correlations and mQTLs on data obtained with the Illumina MethylationEPIC BeadChip (EPIC array) and compared the performance of the EPIC array to the Illumina HumanMethylation450 BeadChip (HM450 array) for buccal-derived DNA. RESULTS: Good-quality EPIC data were obtained for 102 buccal-derived DNA samples from 49 MZ twin pairs (mean age = 7.5 years, range = 1-10). Differences between MZ twins in the cellular content of buccal swabs were a major driver for differences in their DNA methylation profiles, highlighting the importance to adjust for cellular composition in DNA methylation studies of buccal-derived DNA. After adjusting for cellular composition, the genome-wide mean correlation (r) between MZ twins was 0.21 for the EPIC array, and cis mQTL analysis in 84 twins identified 1,296,323 significant associations (FDR 5%), encompassing 33,749 methylation sites and 616,029 genetic variants. MZ twin correlations were slightly larger (p < 2.2 × 10-16) for novel EPIC probes (N = 383,066, mean r = 0.22) compared to probes that are also present on HM450 (N = 406,822, mean r = 0.20). In line with this observation, a larger percentage of novel EPIC probes was associated with genetic variants (novel EPIC probes with significant mQTL 4.7%, HM450 probes with mQTL 3.9%, p < 2.2 × 10-16). Methylation sites with a large MZ correlation and sites associated with mQTLs were most strongly enriched in epithelial cell DNase I hypersensitive sites (DHSs), enhancers, and histone mark H3K4me3. CONCLUSIONS: We conclude that the contribution of familial factors to individual differences in DNA methylation and the effect of mQTLs are larger for novel EPIC probes, especially those within regulatory elements connected to active regions specific to the investigated tissue.

15.
Gynecol Oncol ; 151(2): 243-249, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30194005

RESUMO

OBJECTIVE: Uterine carcinosarcoma (UCS) is a rare and aggressive form of uterine cancer. It is bi-phasic, exhibiting histological features of both malignant epithelial (carcinoma) and mesenchymal (sarcoma) elements, reflected in ambiguity in accepted treatment guidelines. We sought to study the genomic and transcriptomic profiles of these elements individually to gain further insights into the development of these tumors. METHODS: We macro-dissected carcinomatous, sarcomatous, and normal tissues from formalin fixed paraffin embedded uterine samples of 10 UCS patients. Single nucleotide polymorphism microarrays, targeted DNA sequencing and whole-transcriptome RNA-sequencing were performed. Somatic chromosomal alterations (SCAs), point mutation and gene expression profiles were compared between carcinomatous and sarcomatous components. RESULTS: In addition to TP53, other recurrently mutated genes harboring putative driver or loss-of-function mutations included PTEN, FBXW7, FGFR2, KRAS, PIK3CA and CTNNB1, genes known to be involved in UCS. Intra-patient somatic mutation and SCA profiles were highly similar between paired carcinoma and sarcoma samples. An epithelial-mesenchymal transition (EMT) signature tended to differentiate components, with EMT-like status more common in advanced-stage patients exhibiting higher inter-component SCA heterogeneity. CONCLUSIONS: From DNA analysis, our results indicate a monoclonal disease origin for this cohort. Yet expression-derived EMT statuses of the carcinomatous and sarcomatous components were often discrepant, and advanced cases displayed greater genomic heterogeneity. Therefore, separately-profiled components of UCS tumors may better inform disease progression or potential.


Assuntos
Carcinossarcoma/patologia , Neoplasias Uterinas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinossarcoma/genética , Transição Epitelial-Mesenquimal , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Neoplasias Uterinas/genética
16.
Sci Transl Med ; 10(455)2018 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-30135250

RESUMO

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare inherited skin and mucous membrane fragility disorder complicated by early-onset, highly malignant cutaneous squamous cell carcinomas (SCCs). The molecular etiology of RDEB SCC, which arises at sites of sustained tissue damage, is unknown. We performed detailed molecular analysis using whole-exome, whole-genome, and RNA sequencing of 27 RDEB SCC tumors, including multiple tumors from the same patient and multiple regions from five individual tumors. We report that driver mutations were shared with spontaneous, ultraviolet (UV) light-induced cutaneous SCC (UV SCC) and head and neck SCC (HNSCC) and did not explain the early presentation or aggressive nature of RDEB SCC. Instead, endogenous mutation processes associated with apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) deaminases dominated RDEB SCC. APOBEC mutation signatures were enhanced throughout RDEB SCC tumor evolution, relative to spontaneous UV SCC and HNSCC mutation profiles. Sixty-seven percent of RDEB SCC driver mutations was found to emerge as a result of APOBEC and other endogenous mutational processes previously associated with age, potentially explaining a >1000-fold increased incidence and the early onset of these SCCs. Human papillomavirus-negative basal and mesenchymal subtypes of HNSCC harbored enhanced APOBEC mutational signatures and transcriptomes similar to those of RDEB SCC, suggesting that APOBEC deaminases drive other subtypes of SCC. Collectively, these data establish specific mutagenic mechanisms associated with chronic tissue damage. Our findings reveal a cause for cancers arising at sites of persistent inflammation and identify potential therapeutic avenues to treat RDEB SCC.

17.
Addiction ; 113(11): 2073-2086, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30003630

RESUMO

BACKGROUND AND AIMS: Cannabis is one of the most commonly used substances among adolescents and young adults. Earlier age at cannabis initiation is linked to adverse life outcomes, including multi-substance use and dependence. This study estimated the heritability of age at first cannabis use and identified associations with genetic variants. METHODS: A twin-based heritability analysis using 8055 twins from three cohorts was performed. We then carried out a genome-wide association meta-analysis of age at first cannabis use in a discovery sample of 24 953 individuals from nine European, North American and Australian cohorts, and a replication sample of 3735 individuals. RESULTS: The twin-based heritability for age at first cannabis use was 38% [95% confidence interval (CI) = 19-60%]. Shared and unique environmental factors explained 39% (95% CI = 20-56%) and 22% (95% CI = 16-29%). The genome-wide association meta-analysis identified five single nucleotide polymorphisms (SNPs) on chromosome 16 within the calcium-transporting ATPase gene (ATP2C2) at P < 5E-08. All five SNPs are in high linkage disequilibrium (LD) (r2  > 0.8), with the strongest association at the intronic variant rs1574587 (P = 4.09E-09). Gene-based tests of association identified the ATP2C2 gene on 16q24.1 (P = 1.33e-06). Although the five SNPs and ATP2C2 did not replicate, ATP2C2 has been associated with cocaine dependence in a previous study. ATP2B2, which is a member of the same calcium signalling pathway, has been associated previously with opioid dependence. SNP-based heritability for age at first cannabis use was non-significant. CONCLUSION: Age at cannabis initiation appears to be moderately heritable in western countries, and individual differences in onset can be explained by separate but correlated genetic liabilities. The significant association between age of initiation and ATP2C2 is consistent with the role of calcium signalling mechanisms in substance use disorders.

18.
J Pers ; 2018 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-29752830

RESUMO

OBJECTIVE: Loneliness is an aversive response to a discrepancy between desired and actual social relationships and correlates with personality. We investigate the relationship of loneliness and personality in twin family and molecular genetic data. METHOD: Phenotypic correlations between loneliness and the Big Five personality traits were estimated in 29,625 adults, and in a group with genome-wide genotype data (N = 4,222), genetic correlations were obtained. We explored whether genetic correlations may reflect causal relationships by investigating within monozygotic twin pair differences (Npairs = 2,662), by longitudinal within-subject changes in personality and loneliness (N = 4,260-9,238 longitudinal comparisons), and by longitudinal cross-lagged panel analyses (N = 15,628). Finally, we tested whether genetic correlations were due to cross-trait assortative mating (Nspouse pairs = 4,436). RESULTS: The strongest correlations with loneliness were observed for Neuroticism (r = .55) and Extraversion (r = -.33). Only Neuroticism showed a high correlation with loneliness independent of other personality traits (r = .50), so follow-up analyses focused on Neuroticism. The genetic correlation between loneliness and Neuroticism from genotyped variants was .71; a significant reciprocal causal relationship and nonsignificant cross-trait assortative mating imply that this is at least partly due to mediated pleiotropy. CONCLUSIONS: We show that the relationship between loneliness and personality is largely explained by its relationship with Neuroticism, which is substantially genetic in nature.

19.
Twin Res Hum Genet ; 21(3): 203-213, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29792248

RESUMO

OBJECTIVE: The human gut microbiota has been demonstrated to be associated with a number of host phenotypes, including obesity and a number of obesity-associated phenotypes. This study is aimed at further understanding and describing the relationship between the gut microbiota and obesity-associated measurements obtained from human participants. SUBJECTS/METHODS: Here, we utilize genetically informative study designs, including a four-corners design (extremes of genetic risk for BMI and of observed BMI; N = 50) and the BMI monozygotic (MZ) discordant twin pair design (N = 30), in order to help delineate the role of host genetics and the gut microbiota in the development of obesity. RESULTS: Our results highlight a negative association between BMI and alpha diversity of the gut microbiota. The low genetic risk/high BMI group of individuals had a lower gut microbiota alpha diversity when compared to the other three groups. Although the difference in alpha diversity between the lean and heavy groups of the BMI-discordant MZ twin design did not achieve significance, this difference was observed to be in the expected direction, with the heavier participants having a lower average alpha diversity. We have also identified nine OTUs observed to be associated with either a leaner or heavier phenotype, with enrichment for OTUs classified to the Ruminococcaceae and Oxalobacteraceae taxonomic families. CONCLUSION: Our study presents evidence of a relationship between BMI and alpha diversity of the gut microbiota. In addition to these findings, a number of OTUs were found to be significantly associated with host BMI. These findings may highlight separate subtypes of obesity, one driven by genetic factors, the other more heavily influenced by environmental factors.

20.
Invest Ophthalmol Vis Sci ; 59(1): 132-143, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29332125

RESUMO

Purpose: Uveal melanoma (UM) is uniformly refractory to all available systemic chemotherapies, thus creating an urgent need for novel therapeutics. In this study, we investigated the sensitivity of UM cells to ICG-001, a small molecule reported to suppress the Wnt/ß-catenin-mediated transcriptional program. Methods: We used a panel of UM cell lines to examine the effects of ICG-001 on cellular proliferation, migration, and gene expression. In vivo efficacy of ICG-001 was evaluated in a UM xenograft model. Results: ICG-001 exerted strong antiproliferative activity against UM cells, leading to cell cycle arrest, apoptosis, and inhibition of migration. Global gene expression profiling revealed strong suppression of genes associated with cell cycle proliferation, DNA replication, and G1/S transition. Gene set enrichment analysis revealed that ICG-001 suppressed Wnt, mTOR, and MAPK signaling. Strikingly, ICG-001 suppressed the expression of genes associated with UM aggressiveness, including CDH1, CITED1, EMP1, EMP3, SDCBP, and SPARC. Notably, the transcriptomic footprint of ICG-001, when applied to a UM patient dataset, was associated with better clinical outcome. Lastly, ICG-001 exerted anticancer activity against a UM tumor xenograft in mice. Conclusions: Using in vitro and in vivo experiments, we demonstrate that ICG-001 has strong anticancer activity against UM cells and suppresses transcriptional programs critical for the cancer cell. Our results suggest that ICG-001 holds promise and should be examined further as a novel therapeutic agent for UM.


Assuntos
Apoptose/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Genes Neoplásicos/genética , Melanoma/tratamento farmacológico , Neoplasias Experimentais , Pirimidinonas/farmacologia , Neoplasias Uveais/tratamento farmacológico , Animais , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Melanoma/genética , Melanoma/metabolismo , Camundongos Nus , Neoplasias Uveais/genética , Neoplasias Uveais/metabolismo
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