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1.
Psychol Med ; 53(7): 2798-2807, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-34991751

RESUMEN

BACKGROUND: There is evidence for a polygenic contribution to psychosis. One targetable mechanism through which polygenic variation may impact on individuals and interact with the social environment is stress sensitization, characterized by elevated reactivity to minor stressors in daily life. The current study aimed to investigate whether stress reactivity is modified by polygenic risk score for schizophrenia (PRS) in cases with enduring non-affective psychotic disorder, first-degree relatives of cases, and controls. METHODS: We used the experience sampling method to assess minor stressors, negative affect, positive affect and psychotic experiences in 96 cases, 79 first-degree relatives, i.e. siblings, and 73 controls at wave 3 of the Dutch Genetic Risk and Outcome of Psychosis (GROUP) study. Genome-wide data were collected at baseline to calculate PRS. RESULTS: We found that associations of momentary stress with psychotic experiences, but not with negative and positive affect, were modified by PRS and group (all pFWE<0.001). In contrast to our hypotheses, siblings with high PRS reported less intense psychotic experiences in response to momentary stress compared to siblings with low PRS. No differences in magnitude of these associations were observed in cases with high v. low level of PRS. By contrast, controls with high PRS showed more intense psychotic experiences in response to stress compared to those with low PRS. CONCLUSIONS: This tentatively suggests that polygenic risk may operate in different ways than previously assumed and amplify reactivity to stress in unaffected individuals but operate as a resilience factor in relatives by attenuating their stress reactivity.


Asunto(s)
Trastornos Psicóticos , Esquizofrenia , Humanos , Evaluación Ecológica Momentánea , Trastornos Psicóticos/genética , Trastornos Psicóticos/psicología , Esquizofrenia/genética , Factores de Riesgo , Herencia Multifactorial , Estrés Psicológico/genética
2.
Soc Psychiatry Psychiatr Epidemiol ; 58(1): 43-52, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-35913550

RESUMEN

PURPOSE: The health correlates of polygenic risk (PRS-SCZ) and exposome (ES-SCZ) scores for schizophrenia may vary depending on age and sex. We aimed to examine age- and sex-specific associations of PRS-SCZ and ES-SCZ with self-reported health in the general population. METHODS: Participants were from the population-based Netherlands Mental Health Survey and Incidence Study-2 (NEMESIS-2). Mental and physical health were measured with the 36-item Short Form Survey 4 times between 2007 and 2018. The PRS-SCZ and ES-SCZ were respectively calculated from common genetic variants and exposures (cannabis use, winter birth, hearing impairment, and five childhood adversity categories). Moderation by age and sex was examined in linear mixed models. RESULTS: For PRS-SCZ and ES-SCZ analyses, we included 3099 and 6264 participants, respectively (age range 18-65 years; 55.7-56.1% female). Age and sex did not interact with PRS-SCZ. Age moderated the association between ES-SCZ and mental (interaction: p = 0.02) and physical health (p = 0.0007): at age 18, + 1.00 of ES-SCZ was associated with - 0.10 of mental health and - 0.08 of physical health, whereas at age 65, it was associated with - 0.21 and - 0.23, respectively (all units in standard deviations). Sex moderated the association between ES-SCZ and physical health (p < .0001): + 1.00 of ES-SCZ was associated with - 0.19 of physical health among female and - 0.11 among male individuals. CONCLUSION: There were larger associations between higher ES-SCZ and poorer health among female and older individuals. Accounting for these interactions may increase ES-SCZ precision and help uncover populational determinants of environmental influences on health.


Asunto(s)
Esquizofrenia , Humanos , Masculino , Femenino , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Esquizofrenia/epidemiología , Autoinforme , Predisposición Genética a la Enfermedad , Factores de Riesgo , Estudios de Cohortes
3.
Ann Neurol ; 88(4): 796-806, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32627229

RESUMEN

OBJECTIVE: The rs12608932 single nucleotide polymorphism in UNC13A is associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) susceptibility, and may underlie differences in treatment response. We aimed to characterize the clinical, cognitive, behavioral, and neuroimaging phenotype of UNC13A in patients with ALS. METHODS: We included 2,216 patients with ALS without a C9orf72 mutation to identify clinical characteristics associated with the UNC13A polymorphism. A subcohort of 428 patients with ALS was used to study cognitive and behavioral profiles, and 375 patients to study neuroimaging characteristics. Associations were analyzed under an additive genetic model. RESULTS: Genotyping rs12608932 resulted in 854 A/A, 988 A/C, and 374 C/C genotypes. The C allele was associated with a higher age at symptom onset (median years A/A 63.5, A/C 65.6, and C/C 65.5; p < 0.001), more frequent bulbar onset (A/A 29.6%, A/C 31.8%, and C/C 43.1%; p < 0.001), higher incidences of ALS-FTD (A/A 4.3%, A/C 5.2%, and C/C 9.5%; p = 0.003), lower forced vital capacity at diagnosis (median percentage A/A 92.0, A/C 90.0, and C/C 86.5; p < 0.001), and a shorter survival (median in months A/A 33.3, A.C 30.7, and C/C 26.6; p < 0.001). UNC13A was associated with lower scores on ALS-specific cognition tests (means A/A 79.5, A/C 78.1, and C/C 76.6; p = 0.037), and more frequent behavioral disturbances (A/A 16.7%, A/C 24.4%, and C/C 27.7%; p = 0.045). Thinner left inferior temporal and right fusiform cortex were associated with the UNC13A single nucleotide polymorphism (SNP; p = 0.045 and p = 0.036). INTERPRETATION: Phenotypical distinctions associated with UNC13A make it an important factor to take into account in clinical trial design, studies on cognition and behavior, and prognostic counseling. ANN NEUROL 2020;88:796-806.


Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Proteínas del Tejido Nervioso/genética , Anciano , Esclerosis Amiotrófica Lateral/complicaciones , Esclerosis Amiotrófica Lateral/patología , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Polimorfismo de Nucleótido Simple
4.
Pharmacogenomics J ; 20(2): 220-226, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31624333

RESUMEN

Genetic mutations related to amyotrophic lateral sclerosis (ALS) act through distinct pathophysiological pathways, which may lead to varying treatment responses. Here we assess the genetic interaction between C9orf72, UNC13A, and MOBP with creatine and valproic acid treatment in two clinical trials. Genotypic data was available for 309 of the 338 participants (91.4%). The UNC13A genotype affected mortality (p = 0.012), whereas C9orf72 repeat-expansion carriers exhibited a faster rate of decline in overall (p = 0.051) and bulbar functioning (p = 0.005). A dose-response pharmacogenetic interaction was identified between creatine and the A allele of the MOBP genotype (p = 0.027), suggesting a qualitative interaction in a recessive model (HR 3.96, p = 0.015). Not taking genetic information into account may mask evidence of response to treatment or be an unrecognized source of bias. Incorporating genetic data could help investigators to identify critical treatment clues in patients with ALS.


Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Proteína C9orf72/genética , Epistasis Genética/genética , Proteínas de la Mielina/genética , Proteínas del Tejido Nervioso/genética , Farmacogenética/métodos , Esclerosis Amiotrófica Lateral/diagnóstico , Esclerosis Amiotrófica Lateral/epidemiología , Método Doble Ciego , Humanos , Mutación/genética , Países Bajos/epidemiología , Pruebas de Farmacogenómica/métodos
6.
Acta Neuropathol ; 138(2): 237-250, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31131421

RESUMEN

The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target.


Asunto(s)
Demencia/genética , Longevidad/genética , Mutación , Fosfolipasa C gamma/genética , Alelos , Enfermedad de Alzheimer/genética , Esclerosis Amiotrófica Lateral/genética , Encéfalo/inmunología , Encéfalo/metabolismo , Encéfalo/patología , Demencia Frontotemporal/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Enfermedad por Cuerpos de Lewy/genética , Microglía/metabolismo , Esclerosis Múltiple/genética , Neuroimagen , Enfermedad de Parkinson/genética , Riesgo
7.
Hum Genet ; 132(4): 443-50, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23315237

RESUMEN

Genomic copy number variations (CNVs) and increased parental age are both associated with the risk to develop a variety of clinical neuropsychiatric disorders such as autism, schizophrenia and bipolar disorder. At the same time, it has been shown that the rate of transmitted de novo single nucleotide mutations is increased with paternal age. To address whether paternal age also affects the burden of structural genomic deletions and duplications, we examined various types of CNV burden in a large population sample from the Netherlands. Healthy participants with parental age information (n = 6,773) were collected at different University Medical Centers. CNVs were called with the PennCNV algorithm using Illumina genome-wide SNP array data. We observed no evidence in support of a paternal age effect on CNV load in the offspring. Our results were negative for global measures as well as several proxies for de novo CNV events in this unique sample. While recent studies suggest de novo single nucleotide mutation rate to be dominated by the age of the father at conception, our results strongly suggest that at the level of global CNV burden there is no influence of increased paternal age. While it remains possible that local genomic effects may exist for specific phenotypes, this study indicates that global CNV burden and increased father's age may be independent disease risk factors.


Asunto(s)
Algoritmos , Variaciones en el Número de Copia de ADN , Tasa de Mutación , Mutación , Padres , Polimorfismo de Nucleótido Simple , Adulto , Factores de Edad , Anciano , Femenino , Genética de Población , Humanos , Masculino , Persona de Mediana Edad , Países Bajos
8.
JAMA Psychiatry ; 80(2): 181-185, 2023 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-36542388

RESUMEN

Importance: Predictors consistently associated with psychosis liability and course of illness in schizophrenia (SCZ) spectrum disorders (SSD), including the need for clozapine treatment, are lacking. Longitudinally ascertained medication use may empower studies examining associations between polygenic risk scores (PRSs) and pharmacotherapy choices. Objective: To examine associations between PRS-SCZ loading and groups with different liabilities to SSD (individuals with SSD taking clozapine, individuals with SSD taking other antipsychotics, their parents and siblings, and unrelated healthy controls) and between PRS-SCZ and the likelihood of receiving a prescription of clozapine relative to other antipsychotics. Design, Setting, and Participants: This genetic association study was a multicenter, observational cohort study with 6 years of follow-up. Included were individuals diagnosed with SSD who were taking clozapine or other antipsychotics, their parents and siblings, and unrelated healthy controls. Data were collected from 2004 until 2021 and analyzed between October 2021 and September 2022. Exposures: Polygenic risk scores for SCZ. Main Outcomes and Measures: Multinomial logistic regression was used to examine possible differences between groups by computing risk ratios (RRs), ie, ratios of the probability of pertaining to a particular group divided by the probability of healthy control status. We also computed PRS-informed odd ratios (ORs) for clozapine use relative to other antipsychotics. Results: Polygenic risk scores for SCZ were generated for 2344 participants (mean [SD] age, 36.95 years [14.38]; 994 female individuals [42.4%]) who remained after quality control screening (557 individuals with SSD taking clozapine, 350 individuals with SSD taking other antipsychotics during the 6-year follow-up, 542 parents and 574 siblings of individuals with SSD, and 321 unrelated healthy controls). All RRs were significantly different from 1; RRs were highest for individuals with SSD taking clozapine (RR, 3.24; 95% CI, 2.76-3.81; P = 2.47 × 10-46), followed by individuals with SSD taking other antipsychotics (RR, 2.30; 95% CI, 1.95-2.72; P = 3.77 × 10-22), parents (RR, 1.44; 95% CI, 1.25-1.68; P = 1.76 × 10-6), and siblings (RR, 1.40; 95% CI, 1.21-1.63; P = 8.22 × 10-6). Polygenic risk scores for SCZ were positively associated with clozapine vs other antipsychotic use (OR, 1.41; 95% CI, 1.22-1.63; P = 2.98 × 10-6), suggesting a higher likelihood of clozapine prescriptions among individuals with higher PRS-SCZ. Conclusions and Relevance: In this study, PRS-SCZ loading differed between groups of individuals with SSD, their relatives, and unrelated healthy controls, with patients taking clozapine at the far end of PRS-SCZ loading. Additionally, PRS-SCZ was associated with a higher likelihood of clozapine prescribing. Our findings may inform early intervention and prognostic studies of the value of using PRS-SCZ to personalize antipsychotic treatment.


Asunto(s)
Antipsicóticos , Clozapina , Trastornos Psicóticos , Esquizofrenia , Humanos , Femenino , Adulto , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/genética , Esquizofrenia/diagnóstico , Clozapina/efectos adversos , Antipsicóticos/efectos adversos , Trastornos Psicóticos/tratamiento farmacológico , Trastornos Psicóticos/genética , Trastornos Psicóticos/diagnóstico , Factores de Riesgo , Herencia Multifactorial/genética
9.
Psychiatry Res ; 323: 115143, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36948018

RESUMEN

It is unknown how smoking behavior polygenic scores (PRS) relate to psychosis and psychotic symptoms. To elucidate this, genotype and phenotype data were collected from patients with schizophrenia, their unaffected siblings, and healthy controls in a six-year follow-up prospective cohort study. Associations between smoking behaviors, PRS and schizophrenia symptoms were explored using linear mixed-effect models. The mean number of cigarettes smoked per day were 18 for patients, 13 for siblings and 12 for controls. In the overall sample, PRSs-smoking initiation (i.e., ever smoking as a binary phenotype, PRS-SI) were positively associated with positive symptoms, negative symptoms, and depressive symptoms, whereas PRSs-AI (age at regular smoking initiation) were negatively associated with all symptom dimensions, with similar effect sizes. When considering groups separately, PRS were only associated with psychotic symptoms in siblings and controls. In conclusion, unaffected siblings show smoking behaviors at an intermediate level between patients and healthy controls. Additionally, PRS-SI and PRS-AI are associated with all symptom dimensions only in unaffected siblings and healthy controls, possibly owing to the dominant role of other (genetic) risk factors in patients. Future studies may examine mechanisms via which genetic risk for smoking affects mental health symptoms.


Asunto(s)
Trastornos Psicóticos , Esquizofrenia , Humanos , Esquizofrenia/genética , Esquizofrenia/complicaciones , Fumar/genética , Estudios Prospectivos , Hermanos , Trastornos Psicóticos/psicología
10.
Neurobiol Aging ; 122: 76-87, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36521271

RESUMEN

Amyotrophic lateral sclerosis is a heterogeneous, fatal neurodegenerative disease, characterized by motor neuron loss and in 50% of cases also by cognitive and/or behavioral changes. Mendelian forms of ALS comprise approximately 10-15% of cases. The majority is however considered sporadic, but also with a high contribution of genetic risk factors. To explore the contribution of somatic mutations and/or epigenetic changes to disease risk, we performed whole genome sequencing and methylation analyses using samples from multiple tissues on a cohort of 26 monozygotic twins discordant for ALS, followed by in-depth validation and replication experiments. The results of these analyses implicate several mechanisms in ALS pathophysiology, which include a role for de novo mutations, defects in DNA damage repair and accelerated aging.


Asunto(s)
Esclerosis Amiotrófica Lateral , Enfermedades Neurodegenerativas , Humanos , Esclerosis Amiotrófica Lateral/genética , Gemelos Monocigóticos/genética , Mutación/genética , Secuenciación Completa del Genoma
11.
JAMA Ophthalmol ; 141(8): 737-745, 2023 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-37410486

RESUMEN

Importance: Idiopathic multifocal choroiditis (MFC) is poorly understood, thereby hindering optimal treatment and monitoring of patients. Objective: To identify the genes and pathways associated with idiopathic MFC. Design, Setting, and Participants: This was a case-control genome-wide association study (GWAS) and protein study of blood plasma samples conducted from March 2006 to February 2022. This was a multicenter study involving 6 Dutch universities. Participants were grouped into 2 cohorts: cohort 1 consisted of Dutch patients with idiopathic MFC and controls, and cohort 2 consisted of patients with MFC and controls. Plasma samples from patients with idiopathic MFC who had not received treatment were subjected to targeted proteomics. Idiopathic MFC was diagnosed according to the Standardization of Uveitis Nomenclature (SUN) Working Group guidelines for punctate inner choroidopathy and multifocal choroiditis with panuveitis. Data were analyzed from July 2021 to October 2022. Main outcomes and measures: Genetic variants associated with idiopathic MFC and risk variants associated with plasma protein concentrations in patients. Results: This study included a total of 4437 participants in cohort 1 (170 [3.8%] Dutch patients with idiopathic MFC and 4267 [96.2%] controls; mean [SD] age, 55 [18] years; 2443 female [55%]) and 1344 participants in cohort 2 (52 [3.9%] patients with MFC and 1292 [96.1%] controls; 737 male [55%]). The primary GWAS association mapped to the CFH gene with genome-wide significance (lead variant the A allele of rs7535263; odds ratio [OR], 0.52; 95% CI, 0.41-0.64; P = 9.3 × 10-9). There was no genome-wide significant association with classical human leukocyte antigen (HLA) alleles (lead classical allele, HLA-A*31:01; P = .002). The association with rs7535263 showed consistent direction of effect in an independent cohort of 52 cases and 1292 control samples (combined meta-analysis OR, 0.58; 95% CI, 0.38-0.77; P = 3.0 × 10-8). In proteomic analysis of 87 patients, the risk allele G of rs7535263 in the CFH gene was strongly associated with increased plasma concentrations of factor H-related (FHR) proteins (eg, FHR-2, likelihood ratio test, adjusted P = 1.1 × 10-3) and proteins involved in platelet activation and the complement cascade. Conclusions and relevance: Results suggest that CFH gene variants increase systemic concentrations of key factors of the complement and coagulation cascades, thereby conferring susceptibility to idiopathic MFC. These findings suggest that the complement and coagulation pathways may be key targets for the treatment of idiopathic MFC.


Asunto(s)
Coroiditis , Factor H de Complemento , Humanos , Masculino , Femenino , Persona de Mediana Edad , Factor H de Complemento/genética , Coroiditis Multifocal , Estudio de Asociación del Genoma Completo , Proteómica , Polimorfismo de Nucleótido Simple , Coroiditis/diagnóstico , Coroiditis/genética , Proteínas/genética
12.
Nat Commun ; 14(1): 342, 2023 01 20.
Artículo en Inglés | MEDLINE | ID: mdl-36670122

RESUMEN

Amyotrophic lateral sclerosis (ALS) has substantial heritability, in part shared with fronto-temporal dementia (FTD). We show that ALS heritability is enriched in splicing variants and in binding sites of 6 RNA-binding proteins including TDP-43 and FUS. A transcriptome wide association study (TWAS) identified 6 loci associated with ALS, including in NUP50 encoding for the nucleopore basket protein NUP50. Independently, rare variants in NUP50 were associated with ALS risk (P = 3.71.10-03; odds ratio = 3.29; 95%CI, 1.37 to 7.87) in a cohort of 9,390 ALS/FTD patients and 4,594 controls. Cells from one patient carrying a NUP50 frameshift mutation displayed a decreased level of NUP50. Loss of NUP50 leads to death of cultured neurons, and motor defects in Drosophila and zebrafish. Thus, our study identifies alterations in splicing in neurons as critical in ALS and provides genetic evidence linking nuclear pore defects to ALS.


Asunto(s)
Esclerosis Amiotrófica Lateral , Demencia Frontotemporal , Animales , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/metabolismo , Demencia Frontotemporal/genética , Pez Cebra/metabolismo , Neuronas/metabolismo , Proteína FUS de Unión a ARN/genética , Proteína FUS de Unión a ARN/metabolismo , Mutación
13.
BMC Genomics ; 13: 636, 2012 Nov 17.
Artículo en Inglés | MEDLINE | ID: mdl-23157493

RESUMEN

BACKGROUND: The predominant model for regulation of gene expression through DNA methylation is an inverse association in which increased methylation results in decreased gene expression levels. However, recent studies suggest that the relationship between genetic variation, DNA methylation and expression is more complex. RESULTS: Systems genetic approaches for examining relationships between gene expression and methylation array data were used to find both negative and positive associations between these levels. A weighted correlation network analysis revealed that i) both transcriptome and methylome are organized in modules, ii) co-expression modules are generally not preserved in the methylation data and vice-versa, and iii) highly significant correlations exist between co-expression and co-methylation modules, suggesting the existence of factors that affect expression and methylation of different modules (i.e., trans effects at the level of modules). We observed that methylation probes associated with expression in cis were more likely to be located outside CpG islands, whereas specificity for CpG island shores was present when methylation, associated with expression, was under local genetic control. A structural equation model based analysis found strong support in particular for a traditional causal model in which gene expression is regulated by genetic variation via DNA methylation instead of gene expression affecting DNA methylation levels. CONCLUSIONS: Our results provide new insights into the complex mechanisms between genetic markers, epigenetic mechanisms and gene expression. We find strong support for the classical model of genetic variants regulating methylation, which in turn regulates gene expression. Moreover we show that, although the methylation and expression modules differ, they are highly correlated.


Asunto(s)
Células Sanguíneas/metabolismo , Metilación de ADN/genética , Regulación de la Expresión Génica/genética , Variación Genética , Transcriptoma/genética , Células Sanguíneas/química , Islas de CpG/genética , Genotipo , Humanos , Modelos Lineales , Modelos Genéticos , Polimorfismo de Nucleótido Simple/genética
14.
Transl Psychiatry ; 12(1): 219, 2022 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-35650188

RESUMEN

Childhood maltreatment (CM) and genetic vulnerability are both risk factors for psychosis, but the relations between them are not fully understood. Guided by the recent identification of genetic risk to CM, this study investigates the hypothesis that genetic risk to schizophrenia also increases the risk of CM and thus impacts psychosis risk. The relationship between schizophrenia polygenetic risk, CM, and psychotic-like experiences (PLE) was investigated in participants from the Utrecht Cannabis Cohort (N = 1262) and replicated in the independent IMAGEN cohort (N = 1740). Schizophrenia polygenic risk score (SZ-PRS) were calculated from the most recent GWAS. The relationship between CM, PRS, and PLE was first investigated using multivariate linear regression. Next, mediation of CM in the pathway linking SZ-PRS and PLE was examined by structural equation modeling, while adjusting for a set of potential mediators including cannabis use, smoking, and neuroticism. In agreement with previous studies, PLE were strongly associated with SZ-PRS (B = 0.190, p = 0.009) and CM (B = 0.575, p < 0.001). Novel was that CM was also significantly associated with SZ-PRS (B = 0.171, p = 0.001), and substantially mediated the effects of SZ-PRS on PLE (proportion mediated = 29.9%, p = 0.001). In the replication cohort, the analyses yielded similar results, confirming equally strong mediation by CM (proportion mediated = 34.7%, p = 0.009). Our results suggest that CM acts as a mediator in the causal pathway linking SZ-PRS and psychosis risk. These findings open new perspectives on the relations between genetic and environmental risks and warrant further studies into potential interventions to reduce psychosis risk in vulnerable people.


Asunto(s)
Cannabis , Maltrato a los Niños , Trastornos Psicóticos , Esquizofrenia , Niño , Antecedentes Genéticos , Predisposición Genética a la Enfermedad , Humanos , Trastornos Psicóticos/complicaciones , Trastornos Psicóticos/genética , Esquizofrenia/complicaciones , Esquizofrenia/genética , Adulto Joven
15.
Sci Transl Med ; 14(633): eabj0264, 2022 02 23.
Artículo en Inglés | MEDLINE | ID: mdl-35196023

RESUMEN

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study meta-analysis in 9706 samples passing stringent quality control (6763 patients, 2943 controls). We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We then tested 39 DNA methylation-based proxies of putative ALS risk factors and found that high-density lipoprotein cholesterol, body mass index, white blood cell proportions, and alcohol intake were independently associated with ALS. Integration of these results with our latest genome-wide association study showed that cholesterol biosynthesis was potentially causally related to ALS. Last, DNA methylation at several DMPs and blood cell proportion estimates derived from DNA methylation data were associated with survival rate in patients, suggesting that they might represent indicators of underlying disease processes potentially amenable to therapeutic interventions.


Asunto(s)
Esclerosis Amiotrófica Lateral , Enfermedades Neurodegenerativas , Esclerosis Amiotrófica Lateral/genética , Colesterol , Metilación de ADN/genética , Epigénesis Genética , Estudio de Asociación del Genoma Completo , Humanos , Enfermedades Neurodegenerativas/genética
16.
Nat Neurosci ; 25(4): 433-445, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35361972

RESUMEN

The noncoding genome is substantially larger than the protein-coding genome but has been largely unexplored by genetic association studies. Here, we performed region-based rare variant association analysis of >25,000 variants in untranslated regions of 6,139 amyotrophic lateral sclerosis (ALS) whole genomes and the whole genomes of 70,403 non-ALS controls. We identified interleukin-18 receptor accessory protein (IL18RAP) 3' untranslated region (3'UTR) variants as significantly enriched in non-ALS genomes and associated with a fivefold reduced risk of developing ALS, and this was replicated in an independent cohort. These variants in the IL18RAP 3'UTR reduce mRNA stability and the binding of double-stranded RNA (dsRNA)-binding proteins. Finally, the variants of the IL18RAP 3'UTR confer a survival advantage for motor neurons because they dampen neurotoxicity of human induced pluripotent stem cell (iPSC)-derived microglia bearing an ALS-associated expansion in C9orf72, and this depends on NF-κB signaling. This study reveals genetic variants that protect against ALS by reducing neuroinflammation and emphasizes the importance of noncoding genetic association studies.


Asunto(s)
Esclerosis Amiotrófica Lateral , Células Madre Pluripotentes Inducidas , Subunidad beta del Receptor de Interleucina-18/genética , Regiones no Traducidas 3'/genética , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/metabolismo , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Subunidad beta del Receptor de Interleucina-18/metabolismo , Neuronas Motoras/metabolismo
17.
NPJ Genom Med ; 7(1): 8, 2022 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-35091648

RESUMEN

There is a strong genetic contribution to Amyotrophic lateral sclerosis (ALS) risk, with heritability estimates of up to 60%. Both Mendelian and small effect variants have been identified, but in common with other conditions, such variants only explain a little of the heritability. Genomic structural variation might account for some of this otherwise unexplained heritability. We therefore investigated association between structural variation in a set of 25 ALS genes, and ALS risk and phenotype. As expected, the repeat expansion in the C9orf72 gene was identified as associated with ALS. Two other ALS-associated structural variants were identified: inversion in the VCP gene and insertion in the ERBB4 gene. All three variants were associated both with increased risk of ALS and specific phenotypic patterns of disease expression. More than 70% of people with respiratory onset ALS harboured ERBB4 insertion compared with 25% of the general population, suggesting respiratory onset ALS may be a distinct genetic subtype.

18.
Front Cell Neurosci ; 16: 1050596, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36589292

RESUMEN

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of upper and lower motor neurons, leading to progressive weakness of voluntary muscles, with death following from neuromuscular respiratory failure, typically within 3 to 5 years. There is a strong genetic contribution to ALS risk. In 10% or more, a family history of ALS or frontotemporal dementia is obtained, and the Mendelian genes responsible for ALS in such families have now been identified in about 50% of cases. Only about 14% of apparently sporadic ALS is explained by known genetic variation, suggesting that other forms of genetic variation are important. Telomeres maintain DNA integrity during cellular replication, differ between sexes, and shorten naturally with age. Sex and age are risk factors for ALS and we therefore investigated telomere length in ALS. Methods: Samples were from Project MinE, an international ALS whole genome sequencing consortium that includes phenotype data. For validation we used donated brain samples from motor cortex from people with ALS and controls. Ancestry and relatedness were evaluated by principal components analysis and relationship matrices of DNA microarray data. Whole genome sequence data were from Illumina HiSeq platforms and aligned using the Isaac pipeline. TelSeq was used to quantify telomere length using whole genome sequence data. We tested the association of telomere length with ALS and ALS survival using Cox regression. Results: There were 6,580 whole genome sequences, reducing to 6,195 samples (4,315 from people with ALS and 1,880 controls) after quality control, and 159 brain samples (106 ALS, 53 controls). Accounting for age and sex, there was a 20% (95% CI 14%, 25%) increase of telomere length in people with ALS compared to controls (p = 1.1 × 10-12), validated in the brain samples (p = 0.03). Those with shorter telomeres had a 10% increase in median survival (p = 5.0×10-7). Although there was no difference in telomere length between sporadic ALS and familial ALS (p=0.64), telomere length in 334 people with ALS due to expanded C9orf72 repeats was shorter than in those without expanded C9orf72 repeats (p = 5.0×10-4). Discussion: Although telomeres shorten with age, longer telomeres are a risk factor for ALS and worsen prognosis. Longer telomeres are associated with ALS.

19.
Elife ; 102021 11 19.
Artículo en Inglés | MEDLINE | ID: mdl-34796871

RESUMEN

SARM1, a protein with critical NADase activity, is a central executioner in a conserved programme of axon degeneration. We report seven rare missense or in-frame microdeletion human SARM1 variant alleles in patients with amyotrophic lateral sclerosis (ALS) or other motor nerve disorders that alter the SARM1 auto-inhibitory ARM domain and constitutively hyperactivate SARM1 NADase activity. The constitutive NADase activity of these seven variants is similar to that of SARM1 lacking the entire ARM domain and greatly exceeds the activity of wild-type SARM1, even in the presence of nicotinamide mononucleotide (NMN), its physiological activator. This rise in constitutive activity alone is enough to promote neuronal degeneration in response to otherwise non-harmful, mild stress. Importantly, these strong gain-of-function alleles are completely patient-specific in the cohorts studied and show a highly significant association with disease at the single gene level. These findings of disease-associated coding variants that alter SARM1 function build on previously reported genome-wide significant association with ALS for a neighbouring, more common SARM1 intragenic single nucleotide polymorphism (SNP) to support a contributory role of SARM1 in these disorders. A broad phenotypic heterogeneity and variable age-of-onset of disease among patients with these alleles also raises intriguing questions about the pathogenic mechanism of hyperactive SARM1 variants.


Asunto(s)
Esclerosis Amiotrófica Lateral/genética , NAD+ Nucleosidasa/metabolismo , Adulto , Anciano , Alelos , Esclerosis Amiotrófica Lateral/metabolismo , Animales , Proteínas del Dominio Armadillo , Proteínas del Citoesqueleto , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Enfermedad de la Neurona Motora/genética , Enfermedad de la Neurona Motora/metabolismo , Mononucleótido de Nicotinamida/metabolismo
20.
Nat Genet ; 53(12): 1636-1648, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34873335

RESUMEN

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.


Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Estudio de Asociación del Genoma Completo , Mutación , Neuronas/metabolismo , Esclerosis Amiotrófica Lateral/metabolismo , Encéfalo/metabolismo , Colesterol/sangre , Progresión de la Enfermedad , Femenino , Glutamina/metabolismo , Humanos , Masculino , Análisis de la Aleatorización Mendeliana , Repeticiones de Microsatélite , Enfermedades Neurodegenerativas/genética , Sitios de Carácter Cuantitativo , RNA-Seq , Factores de Riesgo
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