RESUMEN
BACKGROUND: Late-onset Alzheimer's disease (AD) is highly heritable. The effect of many common genetic variants, single nucleotide polymorphisms (SNPs), confer risk. Variants are clustered in areas of biology, notably immunity and inflammation, cholesterol metabolism, endocytosis, and ubiquitination. Polygenic scores (PRS), which weight the sum of an individual's risk alleles, have been used to draw inferences about the pathological processes underpinning AD. OBJECTIVE: This paper aims to systematically review how AD PRS are being used to study a range of outcomes and phenotypes related to neurodegeneration. METHODS: We searched the literature from July 2008-July 2018 following PRISMA guidelines. RESULTS: 57 studies met criteria. The AD PRS can distinguish AD cases from controls. The ability of AD PRS to predict conversion from mild cognitive impairment (MCI) to AD was less clear. There was strong evidence of association between AD PRS and cognitive impairment. AD PRS were correlated with a number of biological phenotypes associated with AD pathology, such as neuroimaging changes and amyloid and tau measures. Pathway-specific polygenic scores were also associated with AD-related biologically relevant phenotypes. CONCLUSION: PRS can predict AD effectively and are associated with cognitive impairment. There is also evidence of association between AD PRS and other phenotypes relevant to neurodegeneration. The associations between pathway specific polygenic scores and phenotypic changes may allow us to define the biology of the disease in individuals and indicate who may benefit from specific treatments. Longitudinal cohort studies are required to test the ability of PGS to delineate pathway-specific disease activity.
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Enfermedad de Alzheimer/genética , Herencia Multifactorial/genética , Medicina de Precisión , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas , Humanos , Medicina de Precisión/métodosRESUMEN
INTRODUCTION: Identifying phenotypic manifestations of genetic risk for bipolar disorder (BD) in childhood could increase our understanding of aetiological mechanisms. AIMS: To examine whether BD genetic risk is associated with childhood (age 8 years) cognitive function. METHODS: Using data from the Avon Longitudinal Study of Parents and Children, we examined associations between polygenic risk scores for BD (BD-PRS) derived using Psychiatric Genomics Consortium summary data at p-thresholds (PT) ≤0.01 (primary) and ≤0.5 (secondary) and several cognitive domains (sample sizes 5,613 to 5,936). We also examined whether associations were due to SNPs that have shared risk effects on schizophrenia (SZ). RESULTS: At PT≤0.01, the BD-PRS was associated with poorer executive functioning (ß= -0.03, 95%CI -0.06, -0.01; pâ¯=â¯0.013), and, more weakly with poorer processing speed (ßâ¯=â¯-0.02, 95%CI -0.05, 0.02; pâ¯=â¯0.075). Evidence of association with both poorer processing speed (pâ¯=â¯0.016) and performance IQ (pâ¯=â¯0.018) was stronger at PT≤0.5. Associations with performance IQ and processing speed were primarily driven by genetic effects that are shared with SZ risk, but there was some evidence of bipolar-specific genetic effects on childhood executive functioning. LIMITATIONS: The BD-PRS still explains only a small proportion of the variance for BD which will have reduced power to detect associations. CONCLUSIONS: Genetic risk for BD manifests as impaired cognition in childhood, and this is driven by risk SNPs that are also shared with SZ genetic risk. Further elucidation of which cognitive domains are most affected by genetic risk for BD could help understanding of aetiology and improve prediction of BD.
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Trastorno Bipolar/genética , Trastorno Bipolar/psicología , Cognición , Herencia Multifactorial , Adulto , Niño , Disfunción Cognitiva , Función Ejecutiva , Femenino , Humanos , Estudios Longitudinales , Masculino , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Esquizofrenia/diagnósticoRESUMEN
BACKGROUND: Studying the phenotypic manifestations of increased genetic liability for Bipolar Disorder (BD) can increase understanding of this disorder. AIMS: We assessed whether genetic risk for BD was associated with childhood psychopathology and features of hypomania in young adulthood within a large population-based birth cohort. METHODS: We used data from the second Psychiatric Genetics Consortium Genome Wide Association Study (GWAS) for Bipolar Disorder to construct a polygenic risk score (PRS) for each individual in the Avon Longitudinal Study of Parents and Children (ALSPAC). Linear and logistic regression models were used to assess associations between the BD-PRS and emotional/behavioural difficulties, attention deficit hyperactivity disorder (ADHD) and borderline personality disorder (BPD) traits in childhood, as well as hypomania in early adulthood (sample sizes from 2654 to 6111). RESULTS: The BD-PRS was not associated with total hypomania score, but was weakly associated with a binary measure of hypomania (ORâ¯=â¯1.13, 95%CI 0.98,1.32; pâ¯=â¯0.097), and particularly at higher hypomania symptom thresholds (strongest evidence ORâ¯=â¯1.33, 95%CI 1.07, 1.65; pâ¯=â¯0.01). The BD-PRS was also associated with ADHD (ORâ¯=â¯1.31, 95%CI 1.10, 1.57; pâ¯=â¯0.018), but not with other childhood psychopathology. LIMITATIONS: The PRS only captures common genetic variation and currently explains a relatively small proportion of the variance for BD. CONCLUSIONS: The BD-PRS was associated with ADHD in childhood, and weakly with adult hypomania, but not with other psychopathology examined. Our findings suggest that genetic risk for BD does not appear to manifest in childhood to the same extent as schizophrenia genetic risk has been reported to do.
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Trastorno Bipolar/genética , Predisposición Genética a la Enfermedad , Adolescente , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Trastorno por Déficit de Atención con Hiperactividad/genética , Trastorno de Personalidad Limítrofe/genética , Niño , Femenino , Variación Genética , Estudio de Asociación del Genoma Completo , Humanos , Modelos Logísticos , Estudios Longitudinales , Masculino , Herencia Multifactorial , Fenotipo , Psicopatología , Medición de Riesgo , Esquizofrenia/genética , Adulto JovenRESUMEN
BACKGROUND: Studies involving clinically recruited samples show that genetic liability to schizophrenia overlaps with that for several psychiatric disorders including bipolar disorder, major depression and, in a population study, anxiety disorder and negative symptoms in adolescence.AimsWe examined whether, at a population level, association between schizophrenia liability and anxiety disorders continues into adulthood, for specific anxiety disorders and as a group. We explored in an epidemiologically based cohort the nature of adult psychopathology sharing liability to schizophrenia. METHOD: Schizophrenia polygenic risk scores (PRSs) were calculated for 590 European-descent individuals from the Christchurch Health and Development Study. Logistic regression was used to examine associations between schizophrenia PRS and four anxiety disorders (social phobia, specific phobia, panic disorder and generalised anxiety disorder), schizophrenia/schizophreniform disorder, manic/hypomanic episode, alcohol dependence, major depression, and - using linear regression - total number of anxiety disorders. A novel population-level association with hypomania was tested in a UK birth cohort (Avon Longitudinal Study of Parents and Children). RESULTS: Schizophrenia PRS was associated with total number of anxiety disorders and with generalised anxiety disorder and panic disorder. We show a novel population-level association between schizophrenia PRS and manic/hypomanic episode. CONCLUSIONS: The relationship between schizophrenia liability and anxiety disorders is not restricted to psychopathology in adolescence but is present in adulthood and specifically linked to generalised anxiety disorder and panic disorder. We suggest that the association between schizophrenia liability and hypomanic/manic episodes found in clinical samples may not be due to bias.Declarations of interestNone.
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Alcoholismo/epidemiología , Trastornos de Ansiedad/epidemiología , Trastorno Bipolar/epidemiología , Trastorno Depresivo Mayor/epidemiología , Herencia Multifactorial , Esquizofrenia/epidemiología , Adolescente , Adulto , Comorbilidad , Femenino , Humanos , Estudios Longitudinales , Masculino , Nueva Zelanda/epidemiología , Factores de Riesgo , Reino Unido/epidemiología , Adulto JovenRESUMEN
BACKGROUND: Identifying the phenotypic manifestations of increased genetic liability for depression (MDD) and bipolar disorder (BD) can enhance understanding of their aetiology. The polygenic risk score (PRS) derived using data from genome-wide-association-studies can be used to explore how genetic risk is manifest in different samples. AIMS: In this systematic review, we review studies that examine associations between the MDD and BD polygenic risk scores and phenotypic outcomes. METHODS: Following PRISMA guidelines, we searched EMBASE, Medline and PsycINFO (from August 2009 - 14th March 2016) and references of included studies. Study inclusion was based on predetermined criteria and data were extracted independently and in duplicate. RESULTS: Twenty-five studies were included. Overall, both polygenic risk scores were associated with other psychiatric disorders (not the discovery sample disorder) such as depression, schizophrenia and bipolar disorder, greater symptom severity of depression, membership of a creative profession and greater educational attainment. Both depression and bipolar polygenic risk scores explained small amounts of variance in most phenotypes (<â¯2%). LIMITATIONS: Many studies did not report standardised effect sizes. This prevented us from conducting a meta-analysis. CONCLUSIONS: Polygenic risk scores for BD and MDD are associated with a range of phenotypes and outcomes. However, they only explain a small amount of the variation in these phenotypes. Larger discovery and adequately powered target samples are required to increase power of the PRS approach. This could elucidate how genetic risk for bipolar disorder and depression is manifest and contribute meaningfully to stratified medicine.
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Trastorno Bipolar/genética , Depresión/genética , Fenotipo , Trastorno Depresivo Mayor/genética , Humanos , Herencia Multifactorial , Factores de Riesgo , Esquizofrenia/genéticaRESUMEN
Studying the phenotypic manifestations of increased genetic liability for schizophrenia can increase our understanding of this disorder. Specifically, information from alleles identified in genome-wide association studies can be collapsed into a polygenic risk score (PRS) to explore how genetic risk is manifest within different samples. In this systematic review, we provide a comprehensive assessment of studies examining associations between schizophrenia PRS (SZ-PRS) and several phenotypic measures. We searched EMBASE, Medline and PsycINFO (from August 2009-14th March 2016) plus references of included studies, following PRISMA guidelines. Study inclusion was based on predetermined criteria and data were extracted independently and in duplicate. Overall, SZ-PRS was associated with increased risk for psychiatric disorders such as depression and bipolar disorder, lower performance IQ and negative symptoms. SZ-PRS explained up to 6% of genetic variation in psychiatric phenotypes, compared to <0.7% in measures of cognition. Future gains from using the PRS approach may be greater if used for examining phenotypes that are more closely related to biological substrates, for scores based on gene-pathways, and where PRSs are used to stratify individuals for study of treatment response. As it was difficult to interpret findings across studies due to insufficient information provided by many studies, we propose a framework to guide robust reporting of PRS associations in the future.
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Estudio de Asociación del Genoma Completo , Herencia Multifactorial , Fenotipo , Medición de Riesgo , Esquizofrenia/genética , HumanosRESUMEN
BACKGROUND: There is limited understanding of the symptomatic development of bipolar disorder from childhood to early adulthood. AIMS: We assessed whether borderline personality disorder traits, ADHD, and emotional, behavioural and social difficulties during childhood were associated with hypomania assessed in young adulthood. METHOD: We used data from the Avon Longitudinal Study of Parents and Children (ALSPAC), to examine associations between measures of childhood psychopathology and lifetime hypomanic features assessed at age 22-23 years using the Hypomania Checklist-32 (HCL-32; n = 3372). We also conducted a factor analysis of the HCL to identify latent constructs underlying hypomania, and the extent to which childhood psychopathology was associated with these. RESULTS: We identified two factors of the HCL corresponding to energy/mood and risk-taking/irritability. There was evidence of association between childhood borderline personality disorder traits and both hypomania factors, with evidence that the association was stronger with the risk-taking/irritability factor. All individual borderline traits, with the exception of fear of abandonment, were associated with hypomania. There was also evidence of association between most other measures of childhood psychopathology (ADHD, hyperactivity, conduct problems, peer relationship problems and reduced prosocial behaviour) and the risk-taking/irritability factor, but much less consistent evidence of association with the energy/mood factor. LIMITATIONS: The HCL cannot diagnose bipolar disorder and may be subject to reporting bias. CONCLUSIONS: A broad range of childhood psychopathologies may represent early markers of risk for hypomania. Further studies are required to understand the mechanisms underlying these associations, and to inform earlier detection of bipolar disorder.