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1.
Nat Hum Behav ; 2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-32989287

RESUMO

Handedness has been extensively studied because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and the International Handedness Consortium, we conducted a genome-wide association meta-analysis of handedness (N = 1,766,671). We found 41 loci associated (P < 5 × 10-8) with left-handedness and 7 associated with ambidexterity. Tissue-enrichment analysis implicated the CNS in the aetiology of handedness. Pathways including regulation of microtubules and brain morphology were also highlighted. We found suggestive positive genetic correlations between left-handedness and neuropsychiatric traits, including schizophrenia and bipolar disorder. Furthermore, the genetic correlation between left-handedness and ambidexterity is low (rG = 0.26), which implies that these traits are largely influenced by different genetic mechanisms. Our findings suggest that handedness is highly polygenic and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders.

2.
PLoS One ; 15(9): e0238529, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32966289

RESUMO

Amelanotic/hypomelanotic melanoma is a clinicopathologic subtype with absent or minimal melanin. This study assessed previously reported coding variants in albinism genes (TYR, OCA2, TYRP1, SLC45A2, SLC24A5, LRMDA) and common intronic, regulatory variants of OCA2 in individuals with amelanotic/hypomelanotic melanoma, pigmented melanoma cases and controls. Exome sequencing was available for 28 individuals with amelanotic/hypomelanotic melanoma and 303 individuals with pigmented melanoma, which were compared to whole exome data from 1144 Australian controls. Microarray genotyping was available for a further 17 amelanotic/hypomelanotic melanoma, 86 pigmented melanoma, 147 melanoma cases (pigmentation unknown) and 652 unaffected controls. Rare deleterious variants in TYR/OCA1 were more common in amelanotic/hypomelanotic melanoma cases than pigmented melanoma cases (set mixed model association tests P = 0.0088). The OCA2 hypomorphic allele p.V443I was more common in melanoma cases (1.8%) than controls (1.0%, X2 P = 0.02), and more so in amelanotic/hypomelanotic melanoma (4.4%, X2 P = 0.007). No amelanotic/hypomelanotic melanoma cases carried an eye and skin darkening haplotype of OCA2 (including rs7174027), present in 7.1% of pigmented melanoma cases (P = 0.0005) and 9.4% controls. Variants in TYR and OCA2 may play a role in amelanotic/hypomelanotic melanoma susceptibility. We suggest that somatic loss of function at these loci could contribute to the loss of tumor pigmentation, consistent with this we found a higher rate of somatic mutation in TYR/OCA2 in amelanotic/hypomelanotic melanoma vs pigmented melanoma samples (28.6% vs 3.0%; P = 0.021) from The Cancer Genome Atlas Skin Cutaneous Melanoma collection.

3.
Hum Mol Genet ; 29(17): 2976-2985, 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-32716505

RESUMO

Cancers, including cutaneous melanoma, can cluster in families. In addition to environmental etiological factors such as ultraviolet radiation, cutaneous melanoma has a strong genetic component. Genetic risks for cutaneous melanoma range from rare, high-penetrance mutations to common, low-penetrance variants. Known high-penetrance mutations account for only about half of all densely affected cutaneous melanoma families, and the causes of familial clustering in the remainder are unknown. We hypothesize that some clustering is due to the cumulative effect of a large number of variants of individually small effect. Common, low-penetrance genetic risk variants can be combined into polygenic risk scores. We used a polygenic risk score for cutaneous melanoma to compare families without known high-penetrance mutations with unrelated melanoma cases and melanoma-free controls. Family members had significantly higher mean polygenic load for cutaneous melanoma than unrelated cases or melanoma-free healthy controls (Bonferroni-corrected t-test P = 1.5 × 10-5 and 6.3 × 10-45, respectively). Whole genome sequencing of germline DNA from 51 members of 21 families with low polygenic risk for melanoma identified a CDKN2A p.G101W mutation in a single family but no other candidate high-penetrance melanoma susceptibility genes. This work provides further evidence that melanoma, like many other common complex disorders, can arise from the joint action of multiple predisposing factors, including rare high-penetrance mutations, as well as via a combination of large numbers of alleles of small effect.

5.
Twin Res Hum Genet ; 22(5): 277-282, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31608842

RESUMO

A high prevalence of asthma has been documented among the inhabitants of Tristan da Cunha, an isolated island in the South Atlantic. The population derives from just 28 founders. We performed lung function testing, including methacholine inhalation challenge, allergen skin prick testing, and collected DNA from essentially all of the current island population (269 individuals), and genotyped a panel of 43 single-nucleotide polymorphisms (SNPs) reported as associated with asthma and atopy. We carried out a mixed-model association analysis using the known pedigree. There were 96 individuals diagnosed as asthmatic (36%), and heritability estimates were similar to those from nonisolated population samples (multifactorial threshold model, h2 = 48%). The first component from a genetic principal components analysis using the entire SNP panel was nonlinearly associated with asthma, with the maximum risk to those intermediate to reference (Human Genome Diversity Project) European and African samples means. The single most strongly associated SNP was rs2786098 (p = 5.5 × 10-5), known to regulate the gene DENND1B. This explained approximately one-third of the trait heritability, with an allelic odds ratio for the A allele of 2.6. Among A/A carriers, 10 out of 12 individuals were asthmatic. The rs2786098*A variant was initially reported to decrease the risk of childhood (atopic) asthma in European but slightly increase the risk in African-descended populations, and does significantly alter Th2 cell function. Despite an absence of overall association with this variant in recent asthma genome wide association studies meta-analyses, an effect may exist on the particular genetic background of the Tristan da Cunha population.

8.
Twin Res Hum Genet ; 22(2): 79-87, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31012404

RESUMO

Type 2 diabetes (T2D) is a chronic disease that disproportionately affects Indigenous Australians. We have previously reported the localization of a novel T2D locus by linkage analysis to chromosome 2q24 in a large admixed Indigenous Australian pedigree (Busfield et al. (2002). American Journal of Human Genetics, 70, 349-357). Here we describe fine mapping of this region in this pedigree, with the identification of SNPs showing strong association with T2D: rs3845724 (diabetes p = 7 × 10-4), rs4668106 (diabetes p = 9 × 10-4) and rs529002 (plasma glucose p = 3 × 10-4). These associations were successfully replicated in an independent collection of Indigenous Australian T2D cases and controls. These SNPs all lie within the gene encoding ceramide synthase 6 (CERS6) and thus may regulate ceramide synthesis.


Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Proteínas de Membrana/genética , Esfingosina N-Aciltransferase/genética , Austrália/epidemiologia , Diabetes Mellitus Tipo 2/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Polimorfismo de Nucleotídeo Único/genética
11.
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
12.
Genome Res ; 28(11): 1621-1635, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30333196

RESUMO

Most expression quantitative trait locus (eQTL) studies to date have been performed in heterogeneous tissues as opposed to specific cell types. To better understand the cell-type-specific regulatory landscape of human melanocytes, which give rise to melanoma but account for <5% of typical human skin biopsies, we performed an eQTL analysis in primary melanocyte cultures from 106 newborn males. We identified 597,335 cis-eQTL SNPs prior to linkage disequilibrium (LD) pruning and 4997 eGenes (FDR < 0.05). Melanocyte eQTLs differed considerably from those identified in the 44 GTEx tissue types, including skin. Over a third of melanocyte eGenes, including key genes in melanin synthesis pathways, were unique to melanocytes compared to those of GTEx skin tissues or TCGA melanomas. The melanocyte data set also identified trans-eQTLs, including those connecting a pigmentation-associated functional SNP with four genes, likely through cis-regulation of IRF4 Melanocyte eQTLs are enriched in cis-regulatory signatures found in melanocytes as well as in melanoma-associated variants identified through genome-wide association studies. Melanocyte eQTLs also colocalized with melanoma GWAS variants in five known loci. Finally, a transcriptome-wide association study using melanocyte eQTLs uncovered four novel susceptibility loci, where imputed expression levels of five genes (ZFP90, HEBP1, MSC, CBWD1, and RP11-383H13.1) were associated with melanoma at genome-wide significant P-values. Our data highlight the utility of lineage-specific eQTL resources for annotating GWAS findings, and present a robust database for genomic research of melanoma risk and melanocyte biology.


Assuntos
Predisposição Genética para Doença , Melanócitos/metabolismo , Melanoma/genética , Locos de Características Quantitativas , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Proteínas de Transporte/genética , Células Cultivadas , Proteínas Ligantes de Grupo Heme , Hemeproteínas/genética , Humanos , Fatores Reguladores de Interferon/genética , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único
13.
BMJ Open ; 8(9): e025857, 2018 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-30232117

RESUMO

INTRODUCTION: Having many melanocytic naevi or 'moles' on the skin is the strongest predictor of melanoma; thus, much can be learnt from investigating naevi in the general population. We aim to improve the understanding of the epidemiology and biology of naevi by conducting a 3-year prospective study of melanocytic naevi in adults. METHODS AND ANALYSIS: This is a population-based cohort study of melanocytic naevi in 200 adults aged 20-69 years recruited via the Australian electoral roll. At baseline, participants will complete a questionnaire on their sun behaviour and health and undergo a clinical examination. Three-dimensional (3D) total-body photography will be used to record the images of skin lesions. Pigmented naevi will be analysed in terms of number, diameter, colour and border irregularity using automated analysis software (excluding scalp, beneath underwear and soles of feet). All naevi ≥5 mm will be recorded using the integrated dermoscopy photographic system. A saliva sample will be obtained at baseline for genomic DNA analysis of pigmentation, naevus and melanoma-associated genes using the Illumina HumanCoreExome platform. The sun behaviour and health follow-up questionnaire, clinical examination and 3D total-body photography will be repeated every 6 months for 3 years. The first 50 participants will also undergo manual counts of naevi ≥2 mm and ≥5 mm at baseline, 6-month and 12-month follow-ups. Microbiopsy and excision of naevi of research interest is planned to commence at the 18-month time point among those who agree to donate samples for detailed histopathological and molecular assessment. ETHICS AND DISSEMINATION: This study was approved by the Metro South Health Human Research Ethics Committee in April 2016 (approval number: HREC/16/QPAH/125). The findings will be disseminated through peer-reviewed and non-peer-reviewed publications and presentations at conferences.


Assuntos
Nevo Pigmentado/diagnóstico por imagem , Nevo Pigmentado/epidemiologia , Projetos de Pesquisa , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/epidemiologia , Adulto , Idoso , Austrália/epidemiologia , Biópsia , Dermoscopia , Testes Genéticos , Comportamentos de Risco à Saúde , Humanos , Pessoa de Meia-Idade , Nevo Pigmentado/genética , Nevo Pigmentado/patologia , Fotografação , Exame Físico , Estudos Prospectivos , Pele/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Luz Solar , Inquéritos e Questionários , Carga Tumoral , Adulto Jovem
14.
J Alzheimers Dis ; 64(1): 49-54, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29865051

RESUMO

Cohort studies investigating aging and dementia require APOE genotyping. We compared directly measured APOE genotypes to 'hard-call' genotypes derived from imputing genome-wide genotyping data from a range of platforms using several imputation panels. Older GWAS arrays imputed to 1000 Genomes Project (1KGP) phases and the Haplotype Reference Consortium (HRC) reference panels were able to achieve concordance rates of over 98% with stringent quality control (hard-call-threshold 0.8). However, this resulted in high levels of missingness (>12% with 1KGP and 5% with HRC). With recent GWAS arrays, concordance of 99% could be obtained with relatively lenient QC, resulting in no missingness.


Assuntos
Apolipoproteínas E/genética , Polimorfismo de Nucleotídeo Único/genética , Doença de Alzheimer/genética , Estudos de Coortes , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino
15.
Behav Genet ; 48(4): 315-322, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29872974

RESUMO

The extent to which correlations between personality domains and physical and psychological health generalize cross-culturally is unclear. We compared the strength of associations between the personality domains and somatic and psychological distress in Chinese (N = 2069) and a genetically informative sample of Australian (N = 2936) adolescents. We also examined the genetic and environmental etiology between personality, somatic and psychological distress in an Australian sample of 390 monozygotic twins and 698 dizygotic twins. In both populations, personality was assessed using the Junior Eysenck Personality Questionnaire. Somatic and psychological distress was assessed using the Somatic and Psychological Health Report. We found significant cultural differences in the relationship between adolescents' personality traits and somatic and psychological distress. Extraversion was positively associated with somatic distress in the Chinese but not in Australian adolescents. In the Australian twins, genetic covariation between neuroticism and somatic and psychological distress was stronger compared to the genetic associations between either psychoticism or extraversion with psychological distress.


Assuntos
Grupo com Ancestrais do Continente Asiático/psicologia , Extroversão Psicológica , Neuroticismo , Grupo com Ancestrais Oceânicos/psicologia , Estresse Fisiológico , Estresse Psicológico/psicologia , Adolescente , Correlação de Dados , Comparação Transcultural , Feminino , Humanos , Masculino , Modelos Genéticos , Fenótipo , Psicologia do Adolescente , Estudos em Gêmeos como Assunto , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética
16.
Nat Commun ; 9(1): 1684, 2018 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-29739929

RESUMO

The skin's tendency to sunburn rather than tan is a major risk factor for skin cancer. Here we report a large genome-wide association study of ease of skin tanning in 176,678 subjects of European ancestry. We identify significant association with tanning ability at 20 loci. We confirm previously identified associations at six of these loci, and report 14 novel loci, of which ten have never been associated with pigmentation-related phenotypes. Our results also suggest that variants at the AHR/AGR3 locus, previously associated with cutaneous malignant melanoma the underlying mechanism of which is poorly understood, might act on disease risk through modulation of tanning ability.


Assuntos
Proteínas de Transporte/genética , Grupo com Ancestrais do Continente Europeu/genética , Loci Gênicos , Proteínas de Neoplasias/genética , Receptores de Hidrocarboneto Arílico/genética , Queimadura Solar/genética , Bronzeado/genética , Adulto , Idoso , Mapeamento Cromossômico , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Cor de Cabelo/genética , Humanos , Masculino , Melanoma/etiologia , Melanoma/genética , Pessoa de Meia-Idade , Neoplasias Induzidas por Radiação/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Exposição à Radiação , Fatores de Risco , Fatores Sexuais , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/genética , Reino Unido
17.
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
19.
PLoS One ; 12(10): e0186647, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29040338

RESUMO

Changes in dermoscopic patterns of naevi may be associated with melanoma; however, there is no consensus on which dermoscopic classification system is optimal. To determine whether different classification systems give comparable results and can be combined for analysis, we applied two systems to a case-control study of melanoma with 1037 participants: 573 classified using a "1/3 major feature" system, 464 classified based on rules of appearance, and 263 classified with both criteria. There was strong correlation for non-specific (Spearman R = 0.96) and reticular (Spearman R = 0.82) naevi, with a slight bias for globular naevi with the rules of appearance system. Inter-observer reliability was high for the rules of appearance system, particularly for reticular naevi (Pearson >0.97). We show that different classification systems for naevi can be combined for data analysis, and describe a method for determining what adjustments may need to be applied to combine data sets.


Assuntos
Dermoscopia/normas , Melanoma/classificação , Nevo Pigmentado/classificação , Neoplasias Cutâneas/classificação , Adulto , Análise de Variância , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Melanoma/diagnóstico , Melanoma/patologia , Pessoa de Meia-Idade , Nevo Pigmentado/diagnóstico , Nevo Pigmentado/patologia , Variações Dependentes do Observador , Reprodutibilidade dos Testes , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Terminologia como Assunto
20.
Nat Genet ; 49(12): 1752-1757, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29083406

RESUMO

Asthma, hay fever (or allergic rhinitis) and eczema (or atopic dermatitis) often coexist in the same individuals, partly because of a shared genetic origin. To identify shared risk variants, we performed a genome-wide association study (GWAS; n = 360,838) of a broad allergic disease phenotype that considers the presence of any one of these three diseases. We identified 136 independent risk variants (P < 3 × 10-8), including 73 not previously reported, which implicate 132 nearby genes in allergic disease pathophysiology. Disease-specific effects were detected for only six variants, confirming that most represent shared risk factors. Tissue-specific heritability and biological process enrichment analyses suggest that shared risk variants influence lymphocyte-mediated immunity. Six target genes provide an opportunity for drug repositioning, while for 36 genes CpG methylation was found to influence transcription independently of genetic effects. Asthma, hay fever and eczema partly coexist because they share many genetic risk variants that dysregulate the expression of immune-related genes.


Assuntos
Asma/genética , Eczema/genética , Predisposição Genética para Doença/genética , Hipersensibilidade/genética , Rinite Alérgica Sazonal/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único , Fatores de Risco
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