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1.
Artigo em Inglês | MEDLINE | ID: mdl-31666285

RESUMO

BACKGROUND: Alpha-fetoprotein, cancer antigens 15.3, 19.9, 125, carcinoembryonic antigen and alkaline phosphatase are widely measured in attempts to detect cancer and to monitor treatment response. However, due to lack of sensitivity and specificity, their utility is debated. The serum levels of these markers are affected by a number of non-malignant factors, including genotype. Thus, it may be possible to improve both sensitivity and specificity by adjusting test results for genetic effects. METHODS: We performed genome-wide association studies of serum levels of alpha-fetoprotein (N = 22,686), carcinoembryonic antigen (N = 22,309), cancer antigens 15.3 (N = 7,107), 19.9 (N = 9,945) and 125 (N = 9,824), and alkaline phosphatase (N = 162,774). We also examined the correlations between levels of these biomarkers and the presence of cancer, using data from a nation-wide cancer registry. RESULTS: We report a total of 84 associations of 79 sequence variants with levels of the six biomarkers, explaining between 2.3 and 42.3% of the phenotypic variance. Among the 79 variants, 22 are cis (in- or near the gene encoding the biomarker), 18 have minor allele frequency less than 1%, 31 are coding variants and 7 are associated with gene expression in whole blood. We also find multiple conditions associated with higher biomarker levels. CONCLUSIONS: Our results provide insights into the genetic contribution to diversity in concentration of tumor biomarkers in blood. IMPACT: Genetic correction of biomarker values could improve prediction algorithms and decision-making based on these biomarkers.

2.
Nat Commun ; 10(1): 1777, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30992453

RESUMO

Nerve conduction (NC) studies generate measures of peripheral nerve function that can reveal underlying pathology due to axonal loss, demyelination or both. We perform a genome-wide association study of sural NC amplitude and velocity in 7045 Icelanders and find a low-frequency splice-donor variant in PRPH (c.996+1G>A; MAF = 1.32%) associating with decreased NC amplitude but not velocity. PRPH encodes peripherin, an intermediate filament (IF) protein involved in cytoskeletal development and maintenance of neurons. Through RNA and protein studies, we show that the variant leads to loss-of-function (LoF), as when over-expressed in a cell line devoid of other IFs, it does not allow formation of the normal filamentous structure of peripherin, yielding instead punctate protein inclusions. Recall of carriers for neurological assessment confirms that from an early age, homozygotes have significantly lower sural NC amplitude than non-carriers and are at risk of a mild, early-onset, sensory-negative, axonal polyneuropathy.


Assuntos
Condução Nervosa/genética , Periferinas/genética , Polineuropatias/genética , Sítios de Splice de RNA/genética , Nervo Sural/fisiopatologia , Adulto , Idade de Início , Idoso , Axônios/patologia , Estudos de Casos e Controles , Linhagem Celular , Feminino , Seguimentos , Estudo de Associação Genômica Ampla , Homozigoto , Humanos , Islândia/epidemiologia , Mutação com Perda de Função , Masculino , Pessoa de Meia-Idade , Polineuropatias/epidemiologia , Polineuropatias/fisiopatologia , Prevalência , Processamento de RNA/fisiologia
3.
Nat Genet ; 51(2): 237-244, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30643251

RESUMO

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6-11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures.


Assuntos
Consumo de Bebidas Alcoólicas/genética , Fumar/genética , Tabagismo/genética , Feminino , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Risco , Tabaco/efeitos adversos
4.
Nat Genet ; 51(2): 267-276, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30643255

RESUMO

Nasal polyps (NP) are lesions on the nasal and paranasal sinus mucosa and are a risk factor for chronic rhinosinusitis (CRS). We performed genome-wide association studies on NP and CRS in Iceland and the UK (using UK Biobank data) with 4,366 NP cases, 5,608 CRS cases, and >700,000 controls. We found 10 markers associated with NP and 2 with CRS. We also tested 210 markers reported to associate with eosinophil count, yielding 17 additional NP associations. Of the 27 NP signals, 7 associate with CRS and 13 with asthma. Most notably, a missense variant in ALOX15 that causes a p.Thr560Met alteration in arachidonate 15-lipoxygenase (15-LO) confers large genome-wide significant protection against NP (P = 8.0 × 10-27, odds ratio = 0.32; 95% confidence interval = 0.26, 0.39) and CRS (P = 1.1 × 10-8, odds ratio = 0.64; 95% confidence interval = 0.55, 0.75). p.Thr560Met, carried by around 1 in 20 Europeans, was previously shown to cause near total loss of 15-LO enzymatic activity. Our findings identify 15-LO as a potential target for therapeutic intervention in NP and CRS.


Assuntos
Araquidonato 15-Lipoxigenase/genética , Variação Genética/genética , Pólipos Nasais/genética , Sinusite/genética , Adulto , Asma/genética , Doença Crônica , Eosinófilos/patologia , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Islândia , Contagem de Leucócitos/métodos , Masculino , Pólipos Nasais/patologia , Sinusite/patologia
5.
Nat Genet ; 50(12): 1681-1687, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30374069

RESUMO

Osteoarthritis has a highly negative impact on quality of life because of the associated pain and loss of joint function. Here we describe the largest meta-analysis so far of osteoarthritis of the hip and the knee in samples from Iceland and the UK Biobank (including 17,151 hip osteoarthritis patients, 23,877 knee osteoarthritis patients, and more than 562,000 controls). We found 23 independent associations at 22 loci in the additive meta-analyses, of which 16 of the loci were novel: 12 for hip and 4 for knee osteoarthritis. Two associations are between rare or low-frequency missense variants and hip osteoarthritis, affecting the genes SMO (rs143083812, frequency 0.11%, odds ratio (OR) = 2.8, P = 7.9 × 10-12, p.Arg173Cys) and IL11 (rs4252548, frequency 2.08%, OR = 1.30, P = 2.1 × 10-11, p.Arg112His). A common missense variant in the COL11A1 gene also associates with hip osteoarthritis (rs3753841, frequency 61%, P = 5.2 × 10-10, OR = 1.08, p.Pro1284Leu). In addition, using a recessive model, we confirm an association between hip osteoarthritis and a variant of CHADL1 (rs117018441, P = 1.8 × 10-25, OR = 5.9). Furthermore, we observe a complex relationship between height and risk of osteoarthritis.

6.
Nat Genet ; 50(9): 1304-1310, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30104764

RESUMO

Heritability measures the proportion of trait variation that is due to genetic inheritance. Measurement of heritability is important in the nature-versus-nurture debate. However, existing estimates of heritability may be biased by environmental effects. Here, we introduce relatedness disequilibrium regression (RDR), a novel method for estimating heritability. RDR avoids most sources of environmental bias by exploiting variation in relatedness due to random Mendelian segregation. We used a sample of 54,888 Icelanders who had both parents genotyped to estimate the heritability of 14 traits, including height (55.4%, s.e. 4.4%) and educational attainment (17.0%, s.e. 9.4%). Our results suggest that some other estimates of heritability may be inflated by environmental effects.

7.
Science ; 359(6374): 424-428, 2018 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-29371463

RESUMO

Sequence variants in the parental genomes that are not transmitted to a child (the proband) are often ignored in genetic studies. Here we show that nontransmitted alleles can affect a child through their impacts on the parents and other relatives, a phenomenon we call "genetic nurture." Using results from a meta-analysis of educational attainment, we find that the polygenic score computed for the nontransmitted alleles of 21,637 probands with at least one parent genotyped has an estimated effect on the educational attainment of the proband that is 29.9% (P = 1.6 × 10-14) of that of the transmitted polygenic score. Genetic nurturing effects of this polygenic score extend to other traits. Paternal and maternal polygenic scores have similar effects on educational attainment, but mothers contribute more than fathers to nutrition- and heath-related traits.


Assuntos
Desenvolvimento Infantil , Pai/psicologia , Comportamento Materno , Mães/psicologia , Herança Multifatorial , Comportamento Paterno , Alelos , Criança , Escolaridade , Feminino , Genômica , Genótipo , Humanos , Masculino , Relações Pais-Filho
8.
Addict Biol ; 23(1): 485-492, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28231610

RESUMO

We use polygenic risk scores (PRSs) for schizophrenia (SCZ) and bipolar disorder (BPD) to predict smoking, and addiction to nicotine, alcohol or drugs in individuals not diagnosed with psychotic disorders. Using PRSs for 144 609 subjects, including 10 036 individuals admitted for in-patient addiction treatment and 35 754 smokers, we find that diagnoses of various substance use disorders and smoking associate strongly with PRSs for SCZ (P = 5.3 × 10-50 -1.4 × 10-6 ) and BPD (P = 1.7 × 10-9 -1.9 × 10-3 ), showing shared genetic etiology between psychosis and addiction. Using standardized scores for SCZ and BPD scaled to a unit increase doubling the risk of the corresponding disorder, the odds ratios for alcohol and substance use disorders range from 1.19 to 1.31 for the SCZ-PRS, and from 1.07 to 1.29 for the BPD-PRS. Furthermore, we show that as regular smoking becomes more stigmatized and less prevalent, these biological risk factors gain importance as determinants of the behavior.

9.
Nat Commun ; 8: 14265, 2017 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-28223688

RESUMO

Lumbar disc herniation (LDH) is common and often debilitating. Microdiscectomy of herniated lumbar discs (LDHsurg) is performed on the most severe cases to resolve the resulting sciatica. Here we perform a genome-wide association study on 4,748 LDHsurg cases and 282,590 population controls and discover 37 highly correlated markers associating with LDHsurg at 8q24.21 (between CCDC26 and GSDMC), represented by rs6651255[C] (OR=0.81; P=5.6 × 10-12) with a stronger effect among younger patients than older. As rs6651255[C] also associates with height, we performed a Mendelian randomization analysis using height polygenic risk scores as instruments to estimate the effect of height on LDHsurg risk, and found that the marker's association with LDHsurg is much greater than predicted by its effect on height. In light of presented findings, we speculate that the effect of rs6651255 on LDHsurg is driven by susceptibility to developing severe and persistent sciatica upon LDH.


Assuntos
Cromossomos Humanos Par 8/genética , Predisposição Genética para Doença , Variação Genética , Degeneração do Disco Intervertebral/genética , Deslocamento do Disco Intervertebral/genética , Vértebras Lombares/patologia , Ciática/genética , Adulto , Sequência de Bases , Estatura/genética , Demografia , Feminino , Loci Gênicos , Humanos , Degeneração do Disco Intervertebral/cirurgia , Deslocamento do Disco Intervertebral/cirurgia , Vértebras Lombares/cirurgia , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
10.
Proc Natl Acad Sci U S A ; 114(5): E727-E732, 2017 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-28096410

RESUMO

Epidemiological and genetic association studies show that genetics play an important role in the attainment of education. Here, we investigate the effect of this genetic component on the reproductive history of 109,120 Icelanders and the consequent impact on the gene pool over time. We show that an educational attainment polygenic score, POLYEDU, constructed from results of a recent study is associated with delayed reproduction (P < 10-100) and fewer children overall. The effect is stronger for women and remains highly significant after adjusting for educational attainment. Based on 129,808 Icelanders born between 1910 and 1990, we find that the average POLYEDU has been declining at a rate of ∼0.010 standard units per decade, which is substantial on an evolutionary timescale. Most importantly, because POLYEDU only captures a fraction of the overall underlying genetic component the latter could be declining at a rate that is two to three times faster.


Assuntos
Escolaridade , Variação Genética , Adolescente , Adulto , Feminino , Fertilidade , Genoma Humano , Genótipo , Humanos , Islândia , Inteligência , Masculino , Adulto Jovem
11.
Nat Genet ; 49(1): 152-156, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27918536

RESUMO

Personality is influenced by genetic and environmental factors and associated with mental health. However, the underlying genetic determinants are largely unknown. We identified six genetic loci, including five novel loci, significantly associated with personality traits in a meta-analysis of genome-wide association studies (N = 123,132-260,861). Of these genome-wide significant loci, extraversion was associated with variants in WSCD2 and near PCDH15, and neuroticism with variants on chromosome 8p23.1 and in L3MBTL2. We performed a principal component analysis to extract major dimensions underlying genetic variations among five personality traits and six psychiatric disorders (N = 5,422-18,759). The first genetic dimension separated personality traits and psychiatric disorders, except that neuroticism and openness to experience were clustered with the disorders. High genetic correlations were found between extraversion and attention-deficit-hyperactivity disorder (ADHD) and between openness and schizophrenia and bipolar disorder. The second genetic dimension was closely aligned with extraversion-introversion and grouped neuroticism with internalizing psychopathology (e.g., depression or anxiety).


Assuntos
Loci Gênicos/genética , Marcadores Genéticos/genética , Estudo de Associação Genômica Ampla , Transtornos Mentais/genética , Personalidade/genética , Adulto , Idoso , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos
12.
Sci Rep ; 6: 36189, 2016 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-27811963

RESUMO

Only a few common variants in the sequence of the genome have been shown to impact cognitive traits. Here we demonstrate that polygenic scores of educational attainment predict specific aspects of childhood cognition, as measured with IQ. Recently, three sequence variants were shown to associate with educational attainment, a confluence phenotype of genetic and environmental factors contributing to academic success. We show that one of these variants associating with educational attainment, rs4851266-T, also associates with Verbal IQ in dyslexic children (P = 4.3 × 10-4, ß = 0.16 s.d.). The effect of 0.16 s.d. corresponds to 1.4 IQ points for heterozygotes and 2.8 IQ points for homozygotes. We verified this association in independent samples consisting of adults (P = 8.3 × 10-5, ß = 0.12 s.d., combined P = 2.2 x 10-7, ß = 0.14 s.d.). Childhood cognition is unlikely to be affected by education attained later in life, and the variant explains a greater fraction of the variance in verbal IQ than in educational attainment (0.7% vs 0.12%,. P = 1.0 × 10-5).


Assuntos
Cognição , Dislexia/genética , Inteligência/genética , Polimorfismo de Nucleotídeo Único , Sucesso Acadêmico , Adolescente , Adulto , Criança , Cromossomos Humanos Par 2/genética , Bases de Dados Genéticas , Escolaridade , Feminino , Marcadores Genéticos , Humanos , Islândia , Masculino , Herança Multifatorial , Proteínas Nucleares/genética
13.
Nat Genet ; 48(12): 1462-1472, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27798627

RESUMO

The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits.


Assuntos
Ordem de Nascimento , Estudo de Associação Genômica Ampla , Paridade/genética , Locos de Características Quantitativas , Reprodução/genética , Comportamento Reprodutivo/fisiologia , Feminino , Fertilidade/genética , Humanos , Idade Materna , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Gravidez
14.
Nature ; 533(7604): 539-42, 2016 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-27225129

RESUMO

Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.


Assuntos
Encéfalo/metabolismo , Escolaridade , Feto/metabolismo , Regulação da Expressão Gênica/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único/genética , Doença de Alzheimer/genética , Transtorno Bipolar/genética , Cognição , Biologia Computacional , Interação Gene-Ambiente , Humanos , Anotação de Sequência Molecular , Esquizofrenia/genética , Reino Unido
15.
Pain ; 156(11): 2337-53, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26469320

RESUMO

For genetic research to contribute more fully to furthering our knowledge of neuropathic pain, we require an agreed, valid, and feasible approach to phenotyping, to allow collaboration and replication in samples of sufficient size. Results from genetic studies on neuropathic pain have been inconsistent and have met with replication difficulties, in part because of differences in phenotypes used for case ascertainment. Because there is no consensus on the nature of these phenotypes, nor on the methods of collecting them, this study aimed to provide guidelines on collecting and reporting phenotypes in cases and controls for genetic studies. Consensus was achieved through a staged approach: (1) systematic literature review to identify all neuropathic pain phenotypes used in previous genetic studies; (2) Delphi survey to identify the most useful neuropathic pain phenotypes and their validity and feasibility; and (3) meeting of experts to reach consensus on the optimal phenotype(s) to be collected from patients with neuropathic pain for genetic studies. A basic "entry level" set of phenotypes was identified for any genetic study of neuropathic pain. This set identifies cases of "possible" neuropathic pain, and controls, and includes: (1) a validated symptom-based questionnaire to determine whether any pain is likely to be neuropathic; (2) body chart or checklist to identify whether the area of pain distribution is neuroanatomically logical; and (3) details of pain history (intensity, duration, any formal diagnosis). This NeuroPPIC "entry level" set of phenotypes can be expanded by more extensive and specific measures, as determined by scientific requirements and resource availability.


Assuntos
Consenso , Técnica Delfos , Prova Pericial/normas , Cooperação Internacional , Neuralgia , Bases de Dados Bibliográficas/estatística & dados numéricos , Prova Pericial/métodos , Humanos , Neuralgia/diagnóstico , Neuralgia/genética , Neuralgia/fisiopatologia , Medição da Dor , Fenótipo
16.
Nat Neurosci ; 18(7): 953-5, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26053403

RESUMO

We tested whether polygenic risk scores for schizophrenia and bipolar disorder would predict creativity. Higher scores were associated with artistic society membership or creative profession in both Icelandic (P = 5.2 × 10(-6) and 3.8 × 10(-6) for schizophrenia and bipolar disorder scores, respectively) and replication cohorts (P = 0.0021 and 0.00086). This could not be accounted for by increased relatedness between creative individuals and those with psychoses, indicating that creativity and psychosis share genetic roots.


Assuntos
Transtorno Bipolar/genética , Criatividade , Predisposição Genética para Doença/genética , Herança Multifatorial/genética , Transtornos Psicóticos/genética , Sistema de Registros , Esquizofrenia/genética , Estudos de Coortes , Feminino , Humanos , Islândia/epidemiologia , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Risco , Suécia/epidemiologia
17.
Nat Genet ; 47(5): 435-44, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25807286

RESUMO

Here we describe the insights gained from sequencing the whole genomes of 2,636 Icelanders to a median depth of 20×. We found 20 million SNPs and 1.5 million insertions-deletions (indels). We describe the density and frequency spectra of sequence variants in relation to their functional annotation, gene position, pathway and conservation score. We demonstrate an excess of homozygosity and rare protein-coding variants in Iceland. We imputed these variants into 104,220 individuals down to a minor allele frequency of 0.1% and found a recessive frameshift mutation in MYL4 that causes early-onset atrial fibrillation, several mutations in ABCB4 that increase risk of liver diseases and an intronic variant in GNAS associating with increased thyroid-stimulating hormone levels when maternally inherited. These data provide a study design that can be used to determine how variation in the sequence of the human genome gives rise to human diversity.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Cadeias Leves de Miosina/genética , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/genética , Paralisia Bulbar Progressiva/genética , Cromograninas , Feminino , Mutação da Fase de Leitura , Frequência do Gene , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Perda Auditiva Neurossensorial/genética , Humanos , Mutação INDEL , Islândia , Hepatopatias/genética , Masculino , Pessoa de Meia-Idade , Anotação de Sequência Molecular , Filogeografia , Polimorfismo de Nucleotídeo Único , Receptores Acoplados a Proteínas-G/genética , Risco , Análise de Sequência de DNA , Tireotropina/sangue
18.
Pers Individ Dif ; 582014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24415821

RESUMO

Personality traits are major determinants of social behavior influencing various diseases including addiction. Twin and family studies suggest personality and addiction to be under genetic influence. Identification of DNA susceptibility variants relies on valid and reliable phenotyping approaches. We present results of psychometric testing of the Icelandic NEO-FFI in a population sample (N=657) and a sample recruited for a study on addiction genetics (N=3,804). The Icelandic NEO-FFI demonstrated internal consistency and temporal stability. Factor analyses supported the five-factor structure. Icelandic norms were compared to American norms and language translations selected for geographical and cultural proximity to Iceland. Multiple discriminant function analysis using NEO-FFI trait scores and gender as independent variables predicted membership in recruitment groups for 47.3% of addiction study cases (N=3,804), with accurate predictions made for 69.5% of individuals with treated addiction and 43.3% of their first-degree relatives. Correlations between NEO-FFI scores and the discriminant function suggested a combination of high neuroticism, low conscientiousness and low agreeableness predicted membership in the Treated group.

19.
Nature ; 505(7483): 361-6, 2014 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-24352232

RESUMO

In a small fraction of patients with schizophrenia or autism, alleles of copy-number variants (CNVs) in their genomes are probably the strongest factors contributing to the pathogenesis of the disease. These CNVs may provide an entry point for investigations into the mechanisms of brain function and dysfunction alike. They are not fully penetrant and offer an opportunity to study their effects separate from that of manifest disease. Here we show in an Icelandic sample that a few of the CNVs clearly alter fecundity (measured as the number of children by age 45). Furthermore, we use various tests of cognitive function to demonstrate that control subjects carrying the CNVs perform at a level that is between that of schizophrenia patients and population controls. The CNVs do not all affect the same cognitive domains, hence the cognitive deficits that drive or accompany the pathogenesis vary from one CNV to another. Controls carrying the chromosome 15q11.2 deletion between breakpoints 1 and 2 (15q11.2(BP1-BP2) deletion) have a history of dyslexia and dyscalculia, even after adjusting for IQ in the analysis, and the CNV only confers modest effects on other cognitive traits. The 15q11.2(BP1-BP2) deletion affects brain structure in a pattern consistent with both that observed during first-episode psychosis in schizophrenia and that of structural correlates in dyslexia.


Assuntos
Transtorno Autístico/genética , Cognição/fisiologia , Variações do Número de Cópias de DNA/genética , Predisposição Genética para Doença , Esquizofrenia/genética , Adolescente , Adulto , Idoso , Encéfalo/anormalidades , Encéfalo/anatomia & histologia , Encéfalo/metabolismo , Estudos de Casos e Controles , Deleção Cromossômica , Cromossomos Humanos/genética , Cromossomos Humanos Par 15/genética , Dislexia/genética , Feminino , Fertilidade/genética , Heterozigoto , Humanos , Islândia , Transtornos de Aprendizagem/genética , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fenótipo , Adulto Jovem
20.
J Learn Disabil ; 47(6): 532-42, 2014 Nov-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23456983

RESUMO

This article describes psychometric testing of an Icelandic adaptation of the Adult Reading History Questionnaire (ARHQ), designed to detect a history of reading difficulties indicative of dyslexia. Tested in a large and diverse sample of 2,187 adults, the Icelandic adaptation demonstrated internal consistency reliability (Cronbach's alpha = .92) and test-retest reliability (r = .93). Validity was established by comparing scores of adults who as children received ICD-10 diagnoses of specific reading disorder (F81.0; n = 419) to those of adults defined as nondyslexics (n = 679). ROC curve analysis resulted in an area under the curve of .92 (95% CI = .90, .93, p < .001) and a cutoff score of .43 with sensitivity of 84.5% and specificity of 83.7%. An exploratory factor analysis (n = 2,187) suggested three subscales, Dyslexia Symptoms, Current Reading, and Memory, the mean scores of which differed significantly among diagnosed dyslexics, relatives of dyslexics, and population controls. Our results support the applicability of the ARHQ in Icelandic as a self-report screening tool for adult dyslexia in Iceland.


Assuntos
Dislexia/diagnóstico , Psicometria/instrumentação , Leitura , Inquéritos e Questionários/normas , Adulto , Humanos , Islândia , Reprodutibilidade dos Testes
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