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BACKGROUND: Neuroinflammation is involved in the pathophysiology of Alzheimer's disease (AD), including immune-linked genetic variants and molecular pathways, microglia and astrocytes. Multiple Sclerosis (MS) is a chronic, immune-mediated disease with genetic and environmental risk factors and neuropathological features. There are clinical and pathobiological similarities between AD and MS. Here, we investigated shared genetic susceptibility between AD and MS to identify putative pathological mechanisms shared between neurodegeneration and the immune system. METHODS: We analysed GWAS data for late-onset AD (N cases = 64,549, N controls = 634,442) and MS (N cases = 14,802, N controls = 26,703). Gaussian causal mixture modelling (MiXeR) was applied to characterise the genetic architecture and overlap between AD and MS. Local genetic correlation was investigated with Local Analysis of [co]Variant Association (LAVA). The conjunctional false discovery rate (conjFDR) framework was used to identify the specific shared genetic loci, for which functional annotation was conducted with FUMA and Open Targets. RESULTS: MiXeR analysis showed comparable polygenicities for AD and MS (approximately 1800 trait-influencing variants) and genetic overlap with 20% of shared trait-influencing variants despite negligible genetic correlation (rg = 0.03), suggesting mixed directions of genetic effects across shared variants. conjFDR analysis identified 16 shared genetic loci, with 8 having concordant direction of effects in AD and MS. Annotated genes in shared loci were enriched in molecular signalling pathways involved in inflammation and the structural organisation of neurons. CONCLUSIONS: Despite low global genetic correlation, the current results provide evidence for polygenic overlap between AD and MS. The shared loci between AD and MS were enriched in pathways involved in inflammation and neurodegeneration, highlighting new opportunities for future investigation.
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Enfermedad de Alzheimer , Esclerosis Múltiple , Humanos , Esclerosis Múltiple/genética , Enfermedad de Alzheimer/genética , Estudio de Asociación del Genoma Completo , Predisposición Genética a la Enfermedad/genética , Sistema Inmunológico , Sitios Genéticos , Inflamación/genética , Polimorfismo de Nucleótido SimpleRESUMEN
Importance: Premenstrual disorders are heritable, clinically heterogenous, with a range of affective spectrum comorbidities. It is unclear whether genetic predispositions to affective spectrum disorders or other major psychiatric disorders are associated with symptoms of premenstrual disorders. Objective: To assesss whether symptoms of premenstrual disorders are associated with the genetic liability for major psychiatric disorders, as indexed by polygenic risk scores (PRSs). Design, Setting, and Participants: Women from the Norwegian Mother, Father and Child Cohort Study were included in this genetic association study. PRSs were used to determine whether genetic liability for major depression, bipolar disorder, schizophrenia, attention-deficit/hyperactivity disorder, and autism spectrum disorder were associated with the symptoms of premenstrual disorders, using the PRS for height as a somatic comparator. The sample was recruited across Norway between June 1999 and December 2008, and analyses were performed from July 1 to October 14, 2022. Main Outcomes and Measures: The symptoms of premenstrual disorders were assessed at recruitment at week 15 of pregnancy with self-reported severity of depression and irritability before menstruation. Logistic regression was applied to test for the association between the presence of premenstrual disorder symptoms and the PRSs for major psychiatric disorders. Results: The mean (SD) age of 56â¯725 women included in the study was 29.0 (4.6) years. Premenstrual disorder symptoms were present in 12â¯316 of 56â¯725 participants (21.7%). The symptoms of premenstrual disorders were associated with the PRSs for major depression (ß = 0.13; 95% CI, 0.11-0.15; P = 1.21 × 10-36), bipolar disorder (ß = 0.07; 95% CI, 0.05-0.09; P = 1.74 × 10-11), attention deficit/hyperactivity disorder (ß = 0.07; 95% CI, 0.04-0.09; P = 1.58 × 10-9), schizophrenia (ß = 0.11; 95% CI, 0.09-0.13; P = 7.61 × 10-25), and autism spectrum disorder (ß = 0.03; 95% CI, 0.01-0.05; P = .02) but not with the PRS for height. The findings were confirmed in a subsample of women without a history of psychiatric diagnosis. Conclusions: The results of this genetic association study show that genetic liability for both affective spectrum disorder and major psychiatric disorders was associated with symptoms of premenstrual disorders, indicating that premenstrual disorders have overlapping genetic foundations with major psychiatric disorders.
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Trastorno por Déficit de Atención con Hiperactividad , Trastorno del Espectro Autista , Trastorno Bipolar , Trastorno Depresivo Mayor , Niño , Humanos , Femenino , Adulto , Estudios de Cohortes , Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/genética , Trastorno Bipolar/diagnóstico , Trastorno Bipolar/genética , Trastorno Depresivo Mayor/diagnóstico , Trastorno Depresivo Mayor/genética , Factores de Riesgo , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Trastorno por Déficit de Atención con Hiperactividad/genética , Predisposición Genética a la Enfermedad , Herencia Multifactorial/genéticaRESUMEN
Amyloid-beta 42 (Aß42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aß42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aß42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.
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Enfermedad de Alzheimer , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/líquido cefalorraquídeo , Apolipoproteínas E/genética , Biomarcadores/líquido cefalorraquídeo , Proteínas de Ciclo Celular , Humanos , Fragmentos de Péptidos/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Proteínas tau/genéticaRESUMEN
Introduction: Patients with predementia Alzheimer's disease (AD) and at-risk subjects are targets for promising disease-modifying treatments, and improved polygenic risk scores (PRSs) could improve early-stage case selection. Methods: Phenotype-informed PRSs were developed by selecting AD-associated variants conditional on relevant inflammatory or cardiovascular traits. The primary outcome was longitudinal changes in measures of AD pathology, namely development of pathological amyloid deposition, medial temporal lobe atrophy, and cognitive decline in a prospective cohort study including 394 adults without AD dementia. Results: High-risk groups defined by phenotype-informed AD PRSs had significantly steeper volume decline in medial temporal cortices, and the high-risk group defined by the cardiovascular-informed AD PRS had significantly increased hazard ratio of pathological amyloid deposition, compared to low-risk groups. Discussion: AD PRSs informed by inflammatory disorders or cardiovascular risk factors and diseases are associated with development of AD pathology markers and may improve identification of subjects at risk for progression of AD.
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BACKGROUND: Polygenic hazard scores (PHS) estimate age-dependent genetic risk of late-onset Alzheimer's disease (AD), but there is limited information about the performance of PHS on real-world data where the population of interest differs from the model development population and part of the model genotypes are missing or need to be imputed. OBJECTIVE: The aim of this study was to estimate age-dependent risk of late-onset AD using polygenic predictors in Nordic populations. METHODS: We used Desikan PHS model, based on Cox proportional hazards assumption, to obtain age-dependent hazard scores for AD from individual genotypes in the Norwegian DemGene cohort (nâ=â2,772). We assessed the risk discrimination and calibration of Desikan model and extended it by adding new genotype markers (the Desikan Nordic model). Finally, we evaluated both Desikan and Desikan Nordic models in two independent Danish cohorts: The Copenhagen City Heart Study (CCHS) cohort (nâ=â7,643) and The Copenhagen General Population Study (CGPS) cohort (nâ=â10,886). RESULTS: We showed a robust prediction efficiency of Desikan model in stratifying AD risk groups in Nordic populations, even when some of the model SNPs were missing or imputed. We attempted to improve Desikan PHS model by adding new SNPs to it, but we still achieved similar risk discrimination and calibration with the extended model. CONCLUSION: PHS modeling has the potential to guide the timing of treatment initiation based on individual risk profiles and can help enrich clinical trials with people at high risk to AD in Nordic populations.
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Enfermedad de Alzheimer , Edad de Inicio , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/genética , Genotipo , Humanos , Herencia Multifactorial/genética , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Disfunción Cognitiva/psicología , Estudio de Asociación del Genoma Completo , Humanos , Proteínas tau/genéticaRESUMEN
Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.
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Estudio de Asociación del Genoma Completo , Esquizofrenia , Alelos , Predisposición Genética a la Enfermedad/genética , Genómica , Humanos , Polimorfismo de Nucleótido Simple/genética , Esquizofrenia/genéticaRESUMEN
Lithium is the first-line treatment for bipolar disorder (BD), but there is a large variation in response rate and adverse effects. Although the molecular effects of lithium have been studied extensively, the specific mechanisms of action remain unclear. In particular, the molecular changes underlying lithium adverse effects are little known. Multiple linear regression analyses of lithium serum concentrations and global gene expression levels in whole blood were carried out using a large case-control sample (n = 1450). Self-reported adverse effects of lithium were assessed with the "Udvalg for Kliniske Undersøgelser" (UKU) adverse effect rating scale, and regression analysis was used to identify significant associations between lithium-related genes and six of the most common adverse effects. Serum concentrations of lithium were significantly associated with the expression levels of 52 genes (FDR < 0.01), largely replicating previous results. We found 32 up-regulated genes and 20 down-regulated genes in lithium users compared to non-users. The down-regulated gene set was enriched for several processes related to the translational machinery. Two adverse effects were significantly associated (p < 0.01) with three or more lithium-associated genes: tremor (FAM13A-AS1, FAR2, ITGAX, RWDD1, and STARD10) and xerostomia (ANKRD13A, FAR2, RPS8, and RWDD1). The adverse effect association with the largest effect was between CAMK1D expression and nausea/vomiting. These results suggest putative transcriptional mechanisms that may predict lithium adverse effects, and could thus have a large potential for informing clinical practice.
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Antipsicóticos/efectos adversos , Antipsicóticos/uso terapéutico , Trastorno Bipolar/tratamiento farmacológico , Expresión Génica/efectos de los fármacos , Litio/efectos adversos , Litio/uso terapéutico , Antipsicóticos/sangre , Proteína Quinasa Tipo 1 Dependiente de Calcio Calmodulina/genética , Estudios de Casos y Controles , Estudios de Cohortes , Proteínas Activadoras de GTPasa/genética , Humanos , Entrevistas como Asunto , Litio/sangreRESUMEN
Late-onset Alzheimer's disease is a prevalent age-related polygenic disease that accounts for 50-70% of dementia cases. Currently, only a fraction of the genetic variants underlying Alzheimer's disease have been identified. Here we show that increased sample sizes allowed identification of seven previously unidentified genetic loci contributing to Alzheimer's disease. This study highlights microglia, immune cells and protein catabolism as relevant to late-onset Alzheimer's disease, while identifying and prioritizing previously unidentified genes of potential interest. We anticipate that these results can be included in larger meta-analyses of Alzheimer's disease to identify further genetic variants that contribute to Alzheimer's pathology.
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Enfermedad de Alzheimer/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Humanos , Microglía/citología , Herencia Multifactorial/genética , Polimorfismo de Nucleótido Simple/genética , Proteínas/metabolismo , Proteolisis , Tamaño de la MuestraRESUMEN
Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD with psychosis, AD + P). AD + P affects ~50% of individuals with AD, identifies a subgroup with poor outcomes, and is associated with a greater degree of cognitive impairment and depressive symptoms, compared to subjects without psychosis (AD - P). Although the estimated heritability of AD + P is 61%, genetic sources of risk are unknown. We report a genome-wide meta-analysis of 12,317 AD subjects, 5445 AD + P. Results showed common genetic variation accounted for a significant portion of heritability. Two loci, one in ENPP6 (rs9994623, O.R. (95%CI) 1.16 (1.10, 1.22), p = 1.26 × 10-8) and one spanning the 3'-UTR of an alternatively spliced transcript of SUMF1 (rs201109606, O.R. 0.65 (0.56-0.76), p = 3.24 × 10-8), had genome-wide significant associations with AD + P. Gene-based analysis identified a significant association with APOE, due to the APOE risk haplotype ε4. AD + P demonstrated negative genetic correlations with cognitive and educational attainment and positive genetic correlation with depressive symptoms. We previously observed a negative genetic correlation with schizophrenia; instead, we now found a stronger negative correlation with the related phenotype of bipolar disorder. Analysis of polygenic risk scores supported this genetic correlation and documented a positive genetic correlation with risk variation for AD, beyond the effect of ε4. We also document a small set of SNPs likely to affect risk for AD + P and AD or schizophrenia. These findings provide the first unbiased identification of the association of psychosis in AD with common genetic variation and provide insights into its genetic architecture.
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Enfermedad de Alzheimer , Trastornos Psicóticos , Esquizofrenia , Enfermedad de Alzheimer/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Alucinaciones , Humanos , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro , Polimorfismo de Nucleótido Simple/genética , Trastornos Psicóticos/genética , Esquizofrenia/genéticaRESUMEN
Selective serotonin reuptake inhibitors (SSRIs) are prescribed both to patients with schizophrenia and bipolar disorder. Previous studies have shown associations between SSRI treatment and cardiometabolic alterations. The aim of the present study was to investigate genetic variants associated with cardiometabolic adverse effects in patients treated with SSRIs in a naturalistic setting, using a genome-wide cross-sectional approach in a genetically homogeneous sample. We included and genotyped 1981 individuals with schizophrenia or bipolar disorder, of whom 1180 had information available on the outcomes low-density lipoprotein cholesterol (LDL-cholesterol), high-density lipoprotein cholesterol (HDL-cholesterol), triglycerides, and body mass index (BMI) and investigated interactions between SNPs and SSRI use (N = 246) by conducting a genome-wide GxE analysis. We report 13 genome-wide significant interaction effects of SNPs and SSRI serum concentrations on LDL-cholesterol, HDL-cholesterol, and BMI, located in four distinct genomic loci. This study provides new insight into the pharmacogenetics of SSRI but warrants replication in independent populations.
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Síndrome Metabólico/inducido químicamente , Polimorfismo de Nucleótido Simple/genética , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Adulto , Trastorno Bipolar/tratamiento farmacológico , Trastorno Bipolar/genética , Colesterol/sangre , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Estudios Transversales , Femenino , Estudio de Asociación del Genoma Completo , Técnicas de Genotipaje , Humanos , Masculino , Síndrome Metabólico/genética , Noruega , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/genética , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Triglicéridos/sangreRESUMEN
Abstract. BACKGROUND: Altered expression of the complement component C4A gene is a known risk factor for schizophrenia. Further, predicted brain C4A expression has also been associated with memory function highlighting that altered C4A expression in the brain may be relevant for cognitive and behavioral traits. METHODS: We obtained genetic information and performance measures on seven cognitive tasks for up to 329 773 individuals from the UK Biobank, as well as brain imaging data for a subset of 33 003 participants. Direct genotypes for variants (n = 3213) within the major histocompatibility complex region were used to impute C4 structural variation, from which predicted expression of the C4A and C4B genes in human brain tissue were predicted. We investigated if predicted brain C4A or C4B expression were associated with cognitive performance and brain imaging measures using linear regression analyses. RESULTS: We identified significant negative associations between predicted C4A expression and performance on select cognitive tests, and significant associations with MRI-based cortical thickness and surface area in select regions. Finally, we observed significant inconsistent partial mediation of the effects of predicted C4A expression on cognitive performance, by specific brain structure measures. CONCLUSIONS: These results demonstrate that the C4 risk locus is associated with the central endophenotypes of cognitive performance and brain morphology, even when considered independently of other genetic risk factors and in individuals without mental or neurological disorders.
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An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Clozapine (CLZ) is the superior antipsychotic drug for treatment of schizophrenia, but exhibits an extensive interpatient pharmacokinetic variability. Here, we conducted a genome-wide association study (GWAS) of CLZ serum concentration adjusting for known smoking habits, which is a major nongenetic factor reducing CLZ levels. The study included 484 patients with 10,283 steady-state serum concentrations of CLZ and N-desmethylclozapine, prescribed dosing, co-medications and known smoking habits (n = 422; 9284 serum samples) from a therapeutic drug monitoring (TDM) service. The GWAS analyses were performed with and without smoking habits as covariate, where possible hits were assessed in relation to the target CLZ concentration range applied in the TDM service (300-2500 nmol/L). The smoking-independent analysis of N-desmethylclozapine serum concentration and the CLZ-to-N-desmethylclozapine ratio replicated the previously identified locus on chromosome 4. After adjusting for smoking habits in patients confirmed as 'smokers' (61%) or 'nonsmokers' (39%), a novel variant (rs28379954; minor T>C allele frequency 4.1%; 7.6% CT carriers in the population) within the gene encoding the nuclear factor 1 B-type (NFIB) was significantly associated with reduced CLZ serum concentration (p = 1.68 × 10-8, beta = -0.376; explained variance 7.63%). There was no significant association between rs28379954 and N-desmethylclozapine concentration in the GWAS analysis (p = 5.63 × 10-5). The fraction of CLZ TDM samples below 300 nmol/L was significantly higher in carriers vs. noncarriers of the rs28379954 minor C allele [12.0% (95% CI: 9.4-14.7) vs. 6.2% (95% CI: 5.7-6.8), p < 0.001]. We identified a novel variant in the NFIB gene associated with reduced CLZ levels and increased risk of subtherapeutic serum concentrations. This warrants testing of clinical relevance of screening for this gene variant, and also experimental studies to investigate the biological mechanisms of NFIB involvement in CLZ pharmacokinetics.
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Antipsicóticos , Clozapina , Esquizofrenia , Antipsicóticos/uso terapéutico , Clozapina/uso terapéutico , Estudio de Asociación del Genoma Completo , Humanos , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/genética , FumarRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
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Encéfalo/anatomía & histología , Encéfalo/metabolismo , Drosophila melanogaster/metabolismo , Variación Genética , Estudio de Asociación del Genoma Completo , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/patología , Adulto , Anciano , Animales , Estudios de Cohortes , Drosophila melanogaster/genética , Drosophila melanogaster/crecimiento & desarrollo , Humanos , Imagen por Resonancia Magnética , Persona de Mediana Edad , Tamaño de los ÓrganosRESUMEN
Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable common childhood-onset neurodevelopmental disorder. Some rare copy number variations (CNVs) affect multiple neurodevelopmental disorders such as intellectual disability, autism spectrum disorders (ASD), schizophrenia and ADHD. The aim of this study is to determine to what extent ADHD shares high risk CNV alleles with schizophrenia and ASD. We compiled 19 neuropsychiatric CNVs and test 14, with sufficient power, for association with ADHD in Icelandic and Norwegian samples. Eight associate with ADHD; deletions at 2p16.3 (NRXN1), 15q11.2, 15q13.3 (BP4 & BP4.5-BP5) and 22q11.21, and duplications at 1q21.1 distal, 16p11.2 proximal, 16p13.11 and 22q11.21. Six of the CNVs have not been associated with ADHD before. As a group, the 19 CNVs associate with ADHD (OR = 2.43, P = 1.6 × 10-21), even when comorbid ASD and schizophrenia are excluded from the sample. These results highlight the pleiotropic effect of the neuropsychiatric CNVs and add evidence for ADHD, ASD and schizophrenia being related neurodevelopmental disorders rather than distinct entities.