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1.
Sci Adv ; 7(6)2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33547071

RESUMO

To characterize the genetic basis of facial features in Latin Americans, we performed a genome-wide association study (GWAS) of more than 6000 individuals using 59 landmark-based measurements from two-dimensional profile photographs and ~9,000,000 genotyped or imputed single-nucleotide polymorphisms. We detected significant association of 32 traits with at least 1 (and up to 6) of 32 different genomic regions, more than doubling the number of robustly associated face morphology loci reported until now (from 11 to 23). These GWAS hits are strongly enriched in regulatory sequences active specifically during craniofacial development. The associated region in 1p12 includes a tract of archaic adaptive introgression, with a Denisovan haplotype common in Native Americans affecting particularly lip thickness. Among the nine previously unidentified face morphology loci we identified is the VPS13B gene region, and we show that variants in this region also affect midfacial morphology in mice.

2.
Am J Epidemiol ; 2020 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-33324987

RESUMO

Attention-deficit/hyperactivity disorder (ADHD) is associated with a broad range of physical health problems. Using different research designs to test whether ADHD has a causal role in these associations is of great importance because comorbid health problems further increase the serious social and economic impacts of ADHD. We used two-sample Mendelian randomization (MR) to infer causal relationships between ADHD and previously implicated physical health conditions. Different MR methods were used to test the robustness and plausibility of our findings. Consistent findings were taken forward for bidirectional and multivariable MR. We found evidence of ADHD having a causal effect on childhood obesity (OR (Odds Ratio):1.29 (95% CI (Confidence Intervals):1.02,1.63)) and coronary artery disease (OR:1.11(95% CI:1.03,1.19)) with consistent results across MR approaches. There was further MR evidence for a bidirectional relationship between ADHD and childhood obesity. The relationship with coronary artery disease attenuated when controlling for childhood obesity. There was little evidence for inferring a causal effect on other cardiometabolic, autoimmune, allergic and neurological diseases. Our findings strengthen the argument for effective treatment of children with ADHD. It also suggests that clinicians who manage ADHD need to be aware of the risk of childhood obesity to reduce future risks of coronary artery disease.

3.
PLoS Genet ; 16(10): e1008718, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33045005

RESUMO

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.

4.
Artigo em Inglês | MEDLINE | ID: mdl-32663329

RESUMO

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are generally considered early-onset disorders so most research has therefore tended to focus on children. Differences between ADHD/ASD in adult life and childhood have been noted, but few population-based studies have examined them in adulthood. Furthermore, the interpretation of findings is hampered by changes in measure and from parent report to self-report. METHOD: We examined continuous/trait measures of parent- and self-rated ADHD and ASD in adulthood (age 25 years) in a UK prospective longitudinal sample ALPSAC (the Avon Longitudinal Study of Parents and Children), using many of the same measures that parents reported on in childhood (N = 6,064). Our aim was to investigate these traits in this population for mean-level sex differences, overlaps with other cognitive, learning and communication problems and their associations with polygenic risk scores (PRS) for neuropsychiatric disorders (ADHD, ASD, schizophrenia, depression and anxiety). RESULTS: ADHD and ASD traits in adulthood, as in childhood, showed associations with childhood cognitive, learning and communication problems and adult communication/language measures, although less so for self-ratings than parent-ratings. Males had higher ADHD and ASD trait levels, but this was not as marked as in childhood. In adulthood, ADHD (both parent- and self-rated) and ASD (parent-rated) symptoms showed associations with ADHD PRS; self-reported ADHD also showed association with depression PRS, whereas self-reported ASD did not show strong PRS associations. CONCLUSIONS: Our findings suggest that in young adults, ADHD and ASD symptoms have similar characteristics as they do in childhood. Associations with other cognitive, learning and communication problems, and ADHD PRS were somewhat less pronounced for self-reported adult ADHD and ASD symptoms, suggesting that even at age 25, parent reports, where available, could be clinically useful.

5.
Int J Epidemiol ; 49(4): 1282-1293, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32373937

RESUMO

BACKGROUND: Previous studies have found that children born with a non-syndromic orofacial cleft have lower-than-average educational attainment. Differences could be due to a genetic predisposition to low intelligence and academic performance, factors arising due to the cleft phenotype (such as social stigmatization, impaired speech/language development) or confounding by the prenatal environment. A clearer understanding of this mechanism will inform interventions to improve educational attainment in individuals born with a cleft, which could substantially improve their quality of life. We assessed evidence for the hypothesis that common variant genetic liability to non-syndromic cleft lip with or without cleft palate (nsCL/P) influences educational attainment. METHODS: We performed a genome-wide association study (GWAS) meta-analysis of nsCL/P with 1692 nsCL/P cases and 4259 parental and unrelated controls. Using GWAS summary statistics, we performed Linkage Disequilibrium (LD)-score regression to estimate the genetic correlation between nsCL/P, educational attainment (GWAS n = 766 345) and intelligence (GWAS n = 257 828). We used two-sample Mendelian randomization to evaluate the causal effects of genetic liability to nsCL/P on educational attainment and intelligence. RESULTS: There was limited evidence for shared genetic aetiology or causal relationships between nsCL/P and educational attainment [genetic correlation (rg) -0.05, 95% confidence interval (CI) -0.12 to 0.01, P 0.13; MR estimate (ßMR) -0.002, 95% CI -0.009 to 0.006, P 0.679) or intelligence (rg -0.04, 95% CI -0.13 to 0.04, P 0.34; ßMR -0.009, 95% CI -0.02 to 0.002, P 0.11). CONCLUSIONS: Common variants are unlikely to predispose individuals born with nsCL/P to low educational attainment or intelligence. This is an important first step towards understanding the aetiology of low educational attainment in this group.

6.
PLoS Genet ; 16(5): e1008185, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32392212

RESUMO

Psychiatric disorders are highly heritable and associated with a wide variety of social adversity and physical health problems. Using genetic liability (rather than phenotypic measures of disease) as a proxy for psychiatric disease risk can be a useful alternative for research questions that would traditionally require large cohort studies with long-term follow up. Here we conducted a hypothesis-free phenome-wide association study in about 330,000 participants from the UK Biobank to examine associations of polygenic risk scores (PRS) for five psychiatric disorders (major depression (MDD), bipolar disorder (BP), schizophrenia (SCZ), attention-deficit/ hyperactivity disorder (ADHD) and autism spectrum disorder (ASD)) with 23,004 outcomes in UK Biobank, using the open-source PHESANT software package. There was evidence after multiple testing (p<2.55x10-06) for associations of PRSs with 294 outcomes, most of them attributed to associations of PRSMDD (n = 167) and PRSSCZ (n = 157) with mental health factors. Among others, we found strong evidence of association of higher PRSADHD with 1.1 months younger age at first sexual intercourse [95% confidence interval [CI]: -1.25,-0.92] and a history of physical maltreatment; PRSASD with 0.01% lower erythrocyte distribution width [95%CI: -0.013,-0.007]; PRSSCZ with 0.95 lower odds of playing computer games [95%CI:0.95,0.96]; PRSMDD with a 0.12 points higher neuroticism score [95%CI:0.111,0.135] and PRSBP with 1.03 higher odds of having a university degree [95%CI:1.02,1.03]. We were able to show that genetic liabilities for five major psychiatric disorders associate with long-term aspects of adult life, including socio-demographic factors, mental and physical health. This is evident even in individuals from the general population who do not necessarily present with a psychiatric disorder diagnosis.


Assuntos
Bancos de Espécimes Biológicos/estatística & dados numéricos , Estudo de Associação Genômica Ampla/métodos , Transtornos Mentais/epidemiologia , Transtornos Mentais/genética , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/genética , Transtorno Bipolar/epidemiologia , Transtorno Bipolar/genética , Estudos de Coortes , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/genética , Feminino , Heterogeneidade Genética , Predisposição Genética para Doença , Humanos , Masculino , Herança Multifatorial , Fenótipo , Fatores de Risco , Esquizofrenia/epidemiologia , Esquizofrenia/genética , Fatores Socioeconômicos , Reino Unido/epidemiologia
7.
Psychol Med ; : 1-8, 2020 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-32249726

RESUMO

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is associated with later depression and there is considerable genetic overlap between them. This study investigated if ADHD and ADHD genetic liability are causally related to depression using two different methods. METHODS: First, a longitudinal population cohort design was used to assess the association between childhood ADHD (age 7 years) and recurrent depression in young-adulthood (age 18-25 years) in N = 8310 individuals in the Avon Longitudinal Study of Parents and Children (ALSPAC). Second, two-sample Mendelian randomization (MR) analyses examined relationships between genetic liability for ADHD and depression utilising published Genome-Wide Association Study (GWAS) data. RESULTS: Childhood ADHD was associated with an increased risk of recurrent depression in young-adulthood (OR 1.35, 95% CI 1.05-1.73). MR analyses suggested a causal effect of ADHD genetic liability on major depression (OR 1.21, 95% CI 1.12-1.31). MR findings using a broader definition of depression differed, showing a weak influence on depression (OR 1.07, 95% CI 1.02-1.13). CONCLUSIONS: Our findings suggest that ADHD increases the risk of depression later in life and are consistent with a causal effect of ADHD genetic liability on subsequent major depression. However, findings were different for more broadly defined depression.

8.
Int J Epidemiol ; 49(4): 1163-1172, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32003800

RESUMO

OBJECTIVES: To examine whether educational attainment and intelligence have causal effects on risk of Alzheimer's disease (AD), independently of each other. DESIGN: Two-sample univariable and multivariable Mendelian randomization (MR) to estimate the causal effects of education on intelligence and vice versa, and the total and independent causal effects of both education and intelligence on AD risk. PARTICIPANTS: 17 008 AD cases and 37 154 controls from the International Genomics of Alzheimer's Project (IGAP) consortium. MAIN OUTCOME MEASURE: Odds ratio (OR) of AD per standardized deviation increase in years of schooling (SD = 3.6 years) and intelligence (SD = 15 points on intelligence test). RESULTS: There was strong evidence of a causal, bidirectional relationship between intelligence and educational attainment, with the magnitude of effect being similar in both directions [OR for intelligence on education = 0.51 SD units, 95% confidence interval (CI): 0.49, 0.54; OR for education on intelligence = 0.57 SD units, 95% CI: 0.48, 0.66]. Similar overall effects were observed for both educational attainment and intelligence on AD risk in the univariable MR analysis; with each SD increase in years of schooling and intelligence, odds of AD were, on average, 37% (95% CI: 23-49%) and 35% (95% CI: 25-43%) lower, respectively. There was little evidence from the multivariable MR analysis that educational attainment affected AD risk once intelligence was taken into account (OR = 1.15, 95% CI: 0.68-1.93), but intelligence affected AD risk independently of educational attainment to a similar magnitude observed in the univariate analysis (OR = 0.69, 95% CI: 0.44-0.88). CONCLUSIONS: There is robust evidence for an independent, causal effect of intelligence in lowering AD risk. The causal effect of educational attainment on AD risk is likely to be mediated by intelligence.

9.
Behav Genet ; 50(4): 213-220, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31828458

RESUMO

Psychiatric disorders show phenotypic as well as genetic overlaps. There are however also marked developmental changes throughout childhood. We investigated the extent to which, for a full range of early childhood psychopathology, a general "p" factor was explained by genetic liability, as indexed by multiple different psychiatric polygenic risk scores (PRS) and whether these relationships altered with age. The sample was a UK, prospective, population-based cohort with psychopathology data at age 7 (N = 8161) and age 13 (N = 7017). PRS were generated from large published genome-wide association studies. At both ages, we found evidence for a childhood "p" factor as well as for specific factors. Schizophrenia and attention-deficit/hyperactivity disorder (ADHD) PRS were associated with this general "p" factor at both ages but depression and autism spectrum disorder (ASD) PRS were not. We also found some evidence of associations between schizophrenia, ADHD and depression PRS with specific factors, but these were less robust and there was evidence for developmental changes.

10.
Elife ; 82019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31763980

RESUMO

The human face represents a combined set of highly heritable phenotypes, but knowledge on its genetic architecture remains limited, despite the relevance for various fields. A series of genome-wide association studies on 78 facial shape phenotypes quantified from 3-dimensional facial images of 10,115 Europeans identified 24 genetic loci reaching study-wide suggestive association (p < 5 × 10-8), among which 17 were previously unreported. A follow-up multi-ethnic study in additional 7917 individuals confirmed 10 loci including six unreported ones (padjusted < 2.1 × 10-3). A global map of derived polygenic face scores assembled facial features in major continental groups consistent with anthropological knowledge. Analyses of epigenomic datasets from cranial neural crest cells revealed abundant cis-regulatory activities at the face-associated genetic loci. Luciferase reporter assays in neural crest progenitor cells highlighted enhancer activities of several face-associated DNA variants. These results substantially advance our understanding of the genetic basis underlying human facial variation and provide candidates for future in-vivo functional studies.


Assuntos
Face/anatomia & histologia , Loci Gênicos/genética , Desenvolvimento Maxilofacial/genética , Fenótipo , Adolescente , Adulto , Pontos de Referência Anatômicos , Padronização Corporal/genética , Criança , Pré-Escolar , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Ontologia Genética , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Imageamento Tridimensional , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Adulto Jovem
11.
Int J Epidemiol ; 48(6): 1972-1980, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31056667

RESUMO

OBJECTIVE: Several studies report a polygenic component of risk for Alzheimer's disease. Understanding whether this polygenic signal is associated with educational, cognitive and behavioural outcomes in children could provide an earlier window for intervention. METHODS: We examined whether polygenic risk scores (PRS) at varying P-value thresholds in children from the Avon Longitudinal Study of Parents and Children were associated with academic achievement, cognitive and behavioural measures in childhood and adolescence. RESULTS: We did not detect any evidence that the genome-wide significant PRS (5x10-8) were associated with these outcomes. PRS at the highest P-value threshold examined (P ≤ 5x10-1) were associated with lower academic achievement in adolescents (Key Stage 3; ß: -0.03; 95% confidence interval: -0.05, -0.003) but the effect was attenuated when single nucleotide polymorphisms (SNPs) associated with educational attainment were removed. These PRS were associated with lower IQ (ß: -0.04; 95% CI: -0.07, -0.02) at age 8 years with the effect remaining after removing SNPs associated with educational attainment. CONCLUSIONS: SNPs mediating the biological effects of Alzheimer's disease are unlikely to operate early in life. The evidence of association between PRS for Alzheimer's disease at liberal thresholds and cognitive measures suggest shared genetic pathways between Alzheimer's disease, academic achievement and cognition.


Assuntos
Sucesso Acadêmico , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Adolescente , Criança , Cognição , Feminino , Estudo de Associação Genômica Ampla , Humanos , Testes de Inteligência , Estudos Longitudinais , Masculino , Fenótipo , Estudos Prospectivos , Fatores de Risco , Índice de Gravidade de Doença , Reino Unido/epidemiologia
12.
JAMA Psychiatry ; 76(8): 834-842, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31042271

RESUMO

Importance: Early-life exposures, such as prenatal maternal lifestyle, illnesses, nutritional deficiencies, toxin levels, and adverse birth events, have long been considered potential risk factors for neurodevelopmental disorders in offspring. However, maternal genetic factors could be confounding the association between early-life exposures and neurodevelopmental outcomes in offspring, which makes inferring a causal relationship problematic. Objective: To test whether maternal polygenic risk scores (PRSs) for neurodevelopmental disorders were associated with early-life exposures previously linked to the disorders. Design, Setting, and Participants: In this UK population-based cohort study, 7921 mothers with genotype data from the Avon Longitudinal Study of Parents and Children (ALSPAC) underwent testing for association of maternal PRS for attention-deficit/hyperactivity disorder (ADHD PRS), autism spectrum disorder (ASD PRS), and schizophrenia (SCZ PRS) with 32 early-life exposures. ALSPAC data collection began September 6, 1990, and is ongoing. Data were analyzed for the current study from April 1 to September 1, 2018. Exposures: Maternal ADHD PRS, ASD PRS, and SCZ PRS were calculated using discovery effect size estimates from the largest available genome-wide association study and a significance threshold of P < .05. Main Outcomes and Measures: Outcomes measured included questionnaire data on maternal lifestyle and behavior (eg, smoking, alcohol consumption, body mass index, and maternal age), maternal use of nutritional supplements and medications in pregnancy (eg, acetaminophen, iron, zinc, folic acid, and vitamins), maternal illnesses (eg, diabetes, hypertension, rheumatism, psoriasis, and depression), and perinatal factors (eg, birth weight, preterm birth, and cesarean delivery). Results: Maternal PRSs were available from 7921 mothers (mean [SD] age, 28.5 [4.8] years). The ADHD PRS was associated with multiple prenatal factors, including infections (odds ratio [OR], 1.11; 95% CI, 1.04-1.18), use of acetaminophen during late pregnancy (OR, 1.11; 95% CI, 1.04-1.18), lower blood levels of mercury (ß coefficient, -0.06; 95% CI, -0.11 to -0.02), and higher blood levels of cadmium (ß coefficient, 0.07; 95% CI, 0.05-0.09). Little evidence of associations between ASD PRS or SCZ PRS and prenatal factors or of association between any of the PRSs and adverse birth events was found. Sensitivity analyses revealed consistent results. Conclusions and Relevance: These findings suggest that maternal risk alleles for neurodevelopmental disorders, primarily ADHD, are associated with some pregnancy-related exposures. These findings highlight the need to carefully account for potential genetic confounding and triangulate evidence from different approaches when assessing the effects of prenatal exposures on neurodevelopmental disorders in offspring.

13.
Evid Based Ment Health ; 22(2): 67-71, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30979719

RESUMO

OBJECTIVE: Mendelian randomisation (MR) is a technique that aims to assess causal effects of exposures on disease outcomes. The paper aims to present the main assumptions that underlie MR, the statistical methods used to estimate causal effects and how to account for potential violations of the key assumptions. METHODS: We discuss the key assumptions that should be satisfied in an MR setting. We list the statistical methodologies used in two-sample MR when summary data are available to estimate causal effects (ie, Wald ratio estimator, inverse-variance weighted and maximum likelihood method) and identify/adjust for potential violations of MR assumptions (ie, MR-Egger regression and weighted Median approach). We also present statistical methods and graphical tools used to evaluate the presence of heterogeneity. RESULTS: We use as an illustrative example of a published two-sample MR study, investigating the causal association of body mass index with three psychiatric disorders (ie, bipolar disorder, schizophrenia and major depressive disorder). We highlight the importance of assessing the results of all available methods rather than each method alone. We also demonstrate the impact of heterogeneity in the estimation of the causal effects. CONCLUSIONS: MR is a useful tool to assess causality of risk factors in medical research. Assessment of the key assumptions underlying MR is crucial for a valid interpretation of the results.


Assuntos
Índice de Massa Corporal , Causalidade , Análise da Randomização Mendeliana/métodos , Transtornos Mentais , Estudos Observacionais como Assunto/métodos , Humanos , Transtornos Mentais/etiologia , Transtornos Mentais/genética
14.
J Child Psychol Psychiatry ; 60(8): 866-874, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30908655

RESUMO

BACKGROUND: Children with neurodevelopmental disorders are at increased risk of developing depression. Irritability predicts depression in the general population and is common in children with neurodevelopmental disorders. Thus, it is possible that irritability in children with neurodevelopmental disorders contributes to the link with later depression. This study aimed to (a) examine the association between childhood neurodevelopmental difficulties and adolescent depression and (b) test whether irritability explains this association. METHODS: Children with any neurodevelopmental difficulty at the age of 7-9 (n = 1,697) and a selected, comparison group without any neurodevelopmental difficulty (n = 3,177) were identified from a prospective, UK population-based cohort, the Avon Longitudinal Study of Parents and Children. Neurodevelopmental difficulties were defined as a score in the bottom 5% of the sample on at least one measure of cognitive ability, communication, autism spectrum symptoms, attention-deficit/hyperactivity symptoms, reading or motor coordination. The Development and Well-Being Assessment measured parent-reported child irritability at the age of 7, parent-reported adolescent depression at the age of 10 and 13, and self-reported depression at the age of 15. Depression measures were combined, deriving an outcome of major depressive disorder (MDD) in adolescence. Logistic regression examined the association between childhood neurodevelopmental difficulties and adolescent MDD, controlling for gender. Path analysis estimated the proportion of this association explained by irritability. Analyses were repeated for individual neurodevelopmental problems. RESULTS: Childhood neurodevelopmental difficulties were associated with adolescent MDD (OR = 2.11, 95% CI = 1.24, 3.60, p = .006). Childhood irritability statistically accounted for 42% of this association. On examining each neurodevelopmental difficulty separately, autistic, communication and ADHD problems were each associated with depression, with irritability explaining 29%-51% of these links. CONCLUSIONS: Childhood irritability appears to be a key contributor to the link between childhood neurodevelopmental difficulties and adolescent MDD. High rates of irritability in children with autistic and ADHD difficulties may explain elevated rates of depression in the neurodevelopmental group.


Assuntos
Transtorno Depressivo Maior/epidemiologia , Humor Irritável , Transtornos do Neurodesenvolvimento/epidemiologia , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Espectro Autista/epidemiologia , Criança , Transtornos da Comunicação/epidemiologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Risco , Reino Unido
15.
Transl Psychiatry ; 9(1): 35, 2019 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-30679418

RESUMO

Interpreting polygenic overlap between ADHD and both literacy-related and language-related impairments is challenging as genetic associations might be influenced by indirectly shared genetic factors. Here, we investigate genetic overlap between polygenic ADHD risk and multiple literacy-related and/or language-related abilities (LRAs), as assessed in UK children (N ≤ 5919), accounting for genetically predictable educational attainment (EA). Genome-wide summary statistics on clinical ADHD and years of schooling were obtained from large consortia (N ≤ 326,041). Our findings show that ADHD-polygenic scores (ADHD-PGS) were inversely associated with LRAs in ALSPAC, most consistently with reading-related abilities, and explained ≤1.6% phenotypic variation. These polygenic links were then dissected into both ADHD effects shared with and independent of EA, using multivariable regressions (MVR). Conditional on EA, polygenic ADHD risk remained associated with multiple reading and/or spelling abilities, phonemic awareness and verbal intelligence, but not listening comprehension and non-word repetition. Using conservative ADHD-instruments (P-threshold < 5 × 10-8), this corresponded, for example, to a 0.35 SD decrease in pooled reading performance per log-odds in ADHD-liability (P = 9.2 × 10-5). Using subthreshold ADHD-instruments (P-threshold < 0.0015), these effects became smaller, with a 0.03 SD decrease per log-odds in ADHD risk (P = 1.4 × 10-6), although the predictive accuracy increased. However, polygenic ADHD-effects shared with EA were of equal strength and at least equal magnitude compared to those independent of EA, for all LRAs studied, and detectable using subthreshold instruments. Thus, ADHD-related polygenic links with LRAs are to a large extent due to shared genetic effects with EA, although there is evidence for an ADHD-specific association profile, independent of EA, that primarily involves literacy-related impairments.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Escolaridade , Idioma , Alfabetização , Herança Multifatorial , Adolescente , Criança , Feminino , Estudo de Associação Genômica Ampla , Humanos , Inteligência , Masculino , Análise Multivariada , Polimorfismo de Nucleotídeo Único , Escalas de Graduação Psiquiátrica , Análise de Regressão , Medição de Risco , Reino Unido
16.
Epigenomics ; 11(2): 133-145, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30638414

RESUMO

AIM: To determine if nonsyndromic cleft lip with or without cleft palate (nsCL/P) genetic risk variants influence liability to nsCL/P through gene regulation pathways, such as those involving DNA methylation. MATERIALS & METHODS: nsCL/P genetic summary data and methylation data from four studies were used in conjunction with Mendelian randomization and joint likelihood mapping to investigate potential mediation of nsCL/P genetic variants. RESULTS & CONCLUSION: Evidence was found at VAX1 (10q25.3), LOC146880 (17q23.3) and NTN1 (17p13.1), that liability to nsCL/P and variation in DNA methylation might be driven by the same genetic variant, suggesting that genetic variation at these loci may increase liability to nsCL/P by influencing DNA methylation. Follow-up analyses using different tissues and gene expression data provided further insight into possible biological mechanisms.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Metilação de DNA , Variação Genética , Criança , Fenda Labial/patologia , Fissura Palatina/patologia , Epigênese Genética , Feminino , Proteínas de Homeodomínio/genética , Humanos , Masculino , Análise da Randomização Mendeliana , Netrina-1/genética , Fatores de Transcrição/genética
17.
J Youth Adolesc ; 48(4): 815-827, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30671716

RESUMO

Depression is a common mental illness and research has focused on late childhood and adolescence in an attempt to prevent or reduce later psychopathology and/or social impairments. It is important to establish and study population-averaged trajectories of depressive symptoms across adolescence as this could characterise specific changes in populations and help identify critical points to intervene with treatment. Multilevel growth-curve models were used to explore adolescent trajectories of depressive symptoms in 9301 individuals (57% female) from the Avon Longitudinal Study of Parents and Children, a UK based pregnancy cohort. Trajectories of depressive symptoms were constructed for males and females using the short mood and feelings questionnaire over 8 occasions, between 10 and 22 years old. Critical points of development such as age of peak velocity for depressive symptoms (the age at which depressive symptoms increase most rapidly) and the age of maximum depressive symptoms were also derived. The results suggested that from similar initial levels of depressive symptoms at age 11, females on average experienced steeper increases in depressive symptoms than males over their teenage and adolescent years until around the age of 20 when levels of depressive symptoms plateaued and started to decrease for both sexes. Females on average also had an earlier age of peak velocity of depressive symptoms that occurred at 13.5 years, compared to males who on average had an age of peak velocity at 16 years old. Evidence was less clear for a difference between the ages of maximum depressive symptoms which were on average 19.6 years for females and 20.4 for males. Identifying critical periods for different population subgroups may provide useful knowledge for treating and preventing depression and could be tailored to be time specific for certain groups. Possible explanations and recommendations are discussed.


Assuntos
Depressão/epidemiologia , Adolescente , Adulto , Criança , Feminino , Gráficos de Crescimento , Humanos , Estudos Longitudinais , Masculino , Gravidez , Inquéritos e Questionários , Reino Unido/epidemiologia , Adulto Jovem
18.
Wellcome Open Res ; 4: 125, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31984241

RESUMO

Introduction: Cardiometabolic factors are implicated in the aetiology of Alzheimer's disease and may lie on the pathways linking genetic variants to Alzheimer's disease across the life course. We examined whether polygenic risk scores (PRS) were associated with cardiometabolic health indicators through childhood and adolescence. Methods: In 7,977 participants from the Avon Longitudinal Study of Parents and Children, we tested whether a PRS for Alzheimer's disease was associated with trajectories of cardiometabolic risk factors. We examined trajectories for height at 1-18 years; lean and fat mass at 9-18 years; systolic and diastolic blood pressure at 7-18 years; glucose and C-reactive protein at 9-18 years; insulin at 10-18 years; and high and low-density lipoproteins and triglycerides birth at 18 years. We also examined birthweight and interleukin-6 (IL-6) at age 9 years and physical activity at ages 11, 12, and 15 years. Results: No consistent associations were observed between the PRS excluding genetic variants in the apolipoprotein E gene region and cardiometabolic factors trajectories across childhood and adolescence. Conclusions: We did not detect evidence to suggest that the PRS for Alzheimer's disease acts through childhood and adolescent cardiometabolic risk factors. Further studies should examine whether these associations emerge later in adulthood when variation in cardiometabolic risk factors is likely to be greater.

19.
Front Genet ; 9: 462, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30386375

RESUMO

Historically, craniofacial genetic research has understandably focused on identifying the causes of craniofacial anomalies and it has only been within the last 10 years, that there has been a drive to detail the biological basis of normal-range facial variation. This initiative has been facilitated by the availability of low-cost hi-resolution three-dimensional systems which have the ability to capture the facial details of thousands of individuals quickly and accurately. Simultaneous advances in genotyping technology have enabled the exploration of genetic influences on facial phenotypes, both in the present day and across human history. There are several important reasons for exploring the genetics of normal-range variation in facial morphology.     - Disentangling the environmental factors and relative parental biological contributions to heritable traits can help to answer the age-old question "why we look the way that we do?"     - Understanding the etiology of craniofacial anomalies; e.g., unaffected family members of individuals with non-syndromic cleft lip/palate (nsCL/P) have been shown to differ in terms of normal-range facial variation to the general population suggesting an etiological link between facial morphology and nsCL/P.     - Many factors such as ancestry, sex, eye/hair color as well as distinctive facial features (such as, shape of the chin, cheeks, eyes, forehead, lips, and nose) can be identified or estimated using an individual's genetic data, with potential applications in healthcare and forensics.     - Improved understanding of historical selection and adaptation relating to facial phenotypes, for example, skin pigmentation and geographical latitude.     - Highlighting what is known about shared facial traits, medical conditions and genes.

20.
PLoS Genet ; 14(8): e1007501, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30067744

RESUMO

There is increasing evidence that genetic risk variants for non-syndromic cleft lip/palate (nsCL/P) are also associated with normal-range variation in facial morphology. However, previous analyses are mostly limited to candidate SNPs and findings have not been consistently replicated. Here, we used polygenic risk scores (PRS) to test for genetic overlap between nsCL/P and seven biologically relevant facial phenotypes. Where evidence was found of genetic overlap, we used bidirectional Mendelian randomization (MR) to test the hypothesis that genetic liability to nsCL/P is causally related to implicated facial phenotypes. Across 5,804 individuals of European ancestry from two studies, we found strong evidence, using PRS, of genetic overlap between nsCL/P and philtrum width; a 1 S.D. increase in nsCL/P PRS was associated with a 0.10 mm decrease in philtrum width (95% C.I. 0.054, 0.146; P = 2x10-5). Follow-up MR analyses supported a causal relationship; genetic variants for nsCL/P homogeneously cause decreased philtrum width. In addition to the primary analysis, we also identified two novel risk loci for philtrum width at 5q22.2 and 7p15.2 in our Genome-wide Association Study (GWAS) of 6,136 individuals. Our results support a liability threshold model of inheritance for nsCL/P, related to abnormalities in development of the philtrum.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Lábio/anormalidades , Adolescente , Adulto , Criança , Pré-Escolar , Grupos de Populações Continentais/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Técnicas de Genotipagem , Humanos , Estudos Longitudinais , Herança Multifatorial , Fenótipo , Polimorfismo de Nucleotídeo Único , Adulto Jovem
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