ABSTRACT
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.
Subject(s)
Genome-Wide Association Study , Schizophrenia , Alleles , Genetic Predisposition to Disease/genetics , Genomics , Humans , Polymorphism, Single Nucleotide/genetics , Schizophrenia/geneticsABSTRACT
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.
Subject(s)
Alzheimer Disease , Multiple Sclerosis , Humans , Multiple Sclerosis/genetics , Alzheimer Disease/genetics , Genome-Wide Association Study , Genetic Predisposition to Disease/genetics , Immune System , Genetic Loci , Inflammation/genetics , Polymorphism, Single NucleotideABSTRACT
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.
Subject(s)
Alzheimer Disease , Alzheimer Disease/pathology , Amyloid beta-Peptides/cerebrospinal fluid , Apolipoproteins E/genetics , Biomarkers/cerebrospinal fluid , Cell Cycle Proteins , Humans , Peptide Fragments/cerebrospinal fluid , tau Proteins/cerebrospinal fluid , tau Proteins/geneticsABSTRACT
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.
Subject(s)
Alzheimer Disease , Psychotic Disorders , Schizophrenia , Alzheimer Disease/genetics , Genetic Predisposition to Disease/genetics , Genome-Wide Association Study , Hallucinations , Humans , Oxidoreductases Acting on Sulfur Group Donors , Polymorphism, Single Nucleotide/genetics , Psychotic Disorders/genetics , Schizophrenia/geneticsABSTRACT
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.
Subject(s)
Metabolic Syndrome/chemically induced , Polymorphism, Single Nucleotide/genetics , Selective Serotonin Reuptake Inhibitors/adverse effects , Adult , Bipolar Disorder/drug therapy , Bipolar Disorder/genetics , Cholesterol/blood , Cholesterol, HDL/blood , Cholesterol, LDL/blood , Cross-Sectional Studies , Female , Genome-Wide Association Study , Genotyping Techniques , Humans , Male , Metabolic Syndrome/genetics , Norway , Schizophrenia/drug therapy , Schizophrenia/genetics , Selective Serotonin Reuptake Inhibitors/therapeutic use , Triglycerides/bloodABSTRACT
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.
ABSTRACT
The complement cascade plays a role in synaptic pruning and synaptic plasticity, which seem to be involved in cognitive functions and psychiatric disorders. Genetic variants in the closely related CSMD1 and CSMD2 genes, which are implicated in complement regulation, are associated with schizophrenia. Since patients with schizophrenia often show cognitive impairments, we tested whether variants in CSMD1 and CSMD2 are also associated with cognitive functions per se. We took a discovery-replication approach, using well-characterized Scandinavian cohorts. A total of 1637 SNPs in CSMD1 and 206 SNPs in CSMD2 were tested for association with cognitive functions in the NCNG sample (Norwegian Cognitive NeuroGenetics; n=670). Replication testing of SNPs with p-value<0.001 (7 in CSMD1 and 3 in CSMD2) was carried out in the TOP sample (Thematically Organized Psychosis; n=1025) and the BETULA sample (Betula Longitudinal Study on aging, memory and dementia; n=1742). Finally, we conducted a meta-analysis of these SNPs using all three samples. The previously identified schizophrenia marker in CSMD1 (SNP rs10503253) was also included. The strongest association was observed between the CSMD1 SNP rs2740931 and performance in immediate episodic memory (p-value=5×10-6, minor allele A, MAF 0.48-0.49, negative direction of effect). This association reached the study-wide significance level (p⩽1.2×10-5). SNP rs10503253 was not significantly associated with cognitive functions in our samples. In conclusion, we studied n=3437 individuals and found evidence that a variant in CSMD1 is associated with cognitive function. Additional studies of larger samples with cognitive phenotypes will be needed to further clarify the role of CSMD1 in cognitive phenotypes in health and disease.
Subject(s)
Cognition/physiology , Membrane Proteins/genetics , Adult , Aged , Female , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Neuropsychological Tests , Polymorphism, Single Nucleotide , Schizophrenia/genetics , Tumor Suppressor ProteinsABSTRACT
BACKGROUND: Common variants in the Vaccinia-related kinase 2 (VRK2) gene have been associated with schizophrenia, but the relevance of its encoded protein VRK2 in the disorder remains unclear. AIMS: To identify potential differences in VRK2 gene expression levels between schizophrenia, bipolar disorder, psychosis not otherwise specified (PNOS) and healthy controls. METHOD: VRK2 mRNA level was measured in whole blood in 652 individuals (schizophrenia, n = 201; bipolar disorder, n = 167; PNOS, n = 61; healthy controls, n = 223), and compared across diagnostic categories and subcategories. Additionally, we analysed for association between 1566 VRK2 single nucleotide polymorphisms and mRNA levels. RESULTS: We found lower VRK2 mRNA levels in schizophrenia compared with healthy controls (P<10(-12)), bipolar disorder (P<10(-12)) and PNOS (P = 0.0011), and lower levels in PNOS than in healthy controls (P = 0.0042) and bipolar disorder (P = 0.00026). Expression quantitative trait loci in close proximity to the transcription start site of the short isoforms of the VRK2 gene were identified. CONCLUSIONS: Altered VRK2 gene expression seems specific for schizophrenia and PNOS, which is in accordance with findings from genome-wide association studies. These results suggest that reduced VRK2 mRNA levels are involved in the underlying mechanisms in schizophrenia spectrum disorders.
Subject(s)
Bipolar Disorder/genetics , Protein Serine-Threonine Kinases/metabolism , Psychotic Disorders/genetics , Schizophrenia/genetics , Adult , Female , Humans , Male , Polymorphism, Single Nucleotide , RNA, MessengerABSTRACT
ANK3 gene variants have consistently been associated with bipolar spectrum disorder and schizophrenia spectrum disorder. However, the relevance of its encoded protein, ankyrin-3, in these disorders remains elusive. Here, we show that ANK3 gene expression in blood is significantly increased in bipolar disorder and schizophrenia compared with healthy controls. Additionally, we identified potential cis-acting expression quantitative trait loci located close to the transcription start site of one of the isoforms of the gene. These findings suggest that ANK3 mRNA is an interesting marker for further investigation of the underlying mechanisms in psychotic disorders.
Subject(s)
Ankyrins/genetics , Bipolar Disorder/genetics , Schizophrenia/genetics , Female , Genetic Predisposition to Disease , Genotype , Humans , Male , Polymorphism, Single NucleotideABSTRACT
Loss-of-function mutations in the genes associated with primary microcephaly (MCPH) reduce human brain size by about two-thirds, without producing gross abnormalities in brain organization or physiology and leaving other organs largely unaffected [Woods CG, et al. (2005) Am J Hum Genet 76:717-728]. There is also evidence suggesting that MCPH genes have evolved rapidly in primates and humans and have been subjected to selection in recent human evolution [Vallender EJ, et al. (2008) Trends Neurosci 31:637-644]. Here, we show that common variants of MCPH genes account for some of the common variation in brain structure in humans, independently of disease status. We investigated the correlations of SNPs from four MCPH genes with brain morphometry phenotypes obtained with MRI. We found significant, sex-specific associations between common, nonexonic, SNPs of the genes CDK5RAP2, MCPH1, and ASPM, with brain volume or cortical surface area in an ethnically homogenous Norwegian discovery sample (n = 287), including patients with mental illness. The most strongly associated SNP findings were replicated in an independent North American sample (n = 656), which included patients with dementia. These results are consistent with the view that common variation in brain structure is associated with genetic variants located in nonexonic, presumably regulatory, regions.
Subject(s)
Brain , Microcephaly/genetics , Polymorphism, Single Nucleotide , Adult , Animals , Brain/anatomy & histology , Brain/pathology , Brain Mapping , Female , Genetic Predisposition to Disease , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Molecular Sequence Data , Phenotype , Sex FactorsABSTRACT
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.
Subject(s)
Attention Deficit Disorder with Hyperactivity , Autism Spectrum Disorder , Bipolar Disorder , Depressive Disorder, Major , Child , Humans , Female , Adult , Cohort Studies , Autism Spectrum Disorder/diagnosis , Autism Spectrum Disorder/genetics , Bipolar Disorder/diagnosis , Bipolar Disorder/genetics , Depressive Disorder, Major/diagnosis , Depressive Disorder, Major/genetics , Risk Factors , Attention Deficit Disorder with Hyperactivity/diagnosis , Attention Deficit Disorder with Hyperactivity/epidemiology , Attention Deficit Disorder with Hyperactivity/genetics , Genetic Predisposition to Disease , Multifactorial Inheritance/geneticsABSTRACT
Metabolic and cardiovascular side effects are serious clinical problems related to psychopharmacological treatment, but the underlying mechanisms are mostly unknown. We performed a genome-wide association study of metabolic and cardiovascular risk factors during pharmacological therapy. Twelve indicators of metabolic side effects as well as cardiovascular risk factors were analyzed in a naturalistic sample of 594 patients of Norwegian ancestry. We analyzed interactions between gene variants and three categories of psychopharmacological agents based on their reported potential for side effects. For body mass index (BMI), two significantly associated loci were identified on 8q21.3. There were seven markers in one 30-kb region, and the strongest signal was rs7838490. In another locus 140kb away, six markers were significant, and rs6989402 obtained the strongest signal. Both of these loci are located upstream of the gene matrix metalloproteinase 16 (MMP16). For high density lipoprotein cholesterol (HDL-C), marker rs11615274 on 12q21 was significant. The results highlight three genomic regions potentially harboring susceptibility genes for drug-induced metabolic side effects, identifying MMP16 as a candidate gene. This deserves to be replicated in additional populations to provide more evidence for molecular genetic mechanisms of side effects during psychopharmacological treatment.
Subject(s)
Antidepressive Agents/adverse effects , Antipsychotic Agents/adverse effects , Body Mass Index , Cholesterol, HDL/blood , Genetic Loci/genetics , Genome-Wide Association Study/statistics & numerical data , Matrix Metalloproteinase 16/genetics , Mental Disorders/genetics , Adolescent , Adult , Aged , Blood Glucose/drug effects , Blood Glucose/metabolism , Blood Pressure/drug effects , Blood Pressure/genetics , C-Reactive Protein/metabolism , Cross-Sectional Studies , Female , Genome-Wide Association Study/methods , Genotype , Heart Rate/drug effects , Heart Rate/genetics , Humans , Male , Mental Disorders/blood , Mental Disorders/drug therapy , Middle Aged , Polymorphism, Single Nucleotide , Risk Factors , White People/genetics , White People/psychologyABSTRACT
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.
ABSTRACT
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.
Subject(s)
Antipsychotic Agents/adverse effects , Antipsychotic Agents/therapeutic use , Bipolar Disorder/drug therapy , Gene Expression/drug effects , Lithium/adverse effects , Lithium/therapeutic use , Antipsychotic Agents/blood , Calcium-Calmodulin-Dependent Protein Kinase Type 1/genetics , Case-Control Studies , Cohort Studies , GTPase-Activating Proteins/genetics , Humans , Interviews as Topic , Lithium/bloodABSTRACT
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.
Subject(s)
Alzheimer Disease , Age of Onset , Alzheimer Disease/epidemiology , Alzheimer Disease/genetics , Genotype , Humans , Multifactorial Inheritance/genetics , Polymorphism, Single Nucleotide/geneticsABSTRACT
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.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Cognitive Dysfunction/psychology , Genome-Wide Association Study , Humans , tau Proteins/geneticsABSTRACT
Based on the important role of neurotrophic factors in brain development and plasticity and reports of association between schizophrenia and the gene neurotrophic tyrosine kinase receptor 3 (NTRK3), we investigated associations of bipolar disorder with polymorphisms in NTRK3. Recently, our group reported evidence for a possible association of NTRK3 polymorphisms with hippocampal function and schizophrenia. In the present study, we used a homogenous Norwegian case-control sample (the TOP study) consisting of 194 patients diagnosed with bipolar disorder and 336 healthy controls genotyped on the Affymetrix Genome-wide Human SNP Array 6.0. In total 149 markers were investigated for SNP-disease association. Polymorphisms in over 20 markers were nominally associated with bipolar disorder, covering intron 5 to intron 12. Interestingly, our markers appeared to be located close or within the linkage regions reported in schizophrenia, early-onset major depressive disorder and eating disorder, supporting the hypothesis that some genes influence risk beyond traditional diagnostic boundaries.
Subject(s)
Bipolar Disorder/genetics , Genetic Predisposition to Disease , Introns/genetics , Polymorphism, Single Nucleotide/genetics , Receptor, trkC/genetics , Adolescent , Adult , Aged , Case-Control Studies , Female , Genome-Wide Association Study , Genotype , Humans , Linkage Disequilibrium , Male , Middle Aged , Norway , Young AdultABSTRACT
Genetic variants in ankyrin 3 (ANK3) have recently been shown to be associated with bipolar disorder (BD). We genotyped three ANK3 SNPs previously found to be associated with BD (rs10994336, rs1938526, and rs9804190) in a Scandinavian BD case-control sample (N = 854/2,614). Due to evidence of genetic overlap between BD and schizophrenia (SZ), we also genotyped these three SNPs in a Scandinavian SZ case-control sample (N = 1,073/2,919). Combining our Scandinavian samples with an Icelandic sample (N = 435 BD cases, 651 SZ cases, and 11,491 healthy controls), we found rs10994336 and rs9804190 to be nominally significantly associated with BD in this combined Nordic BD sample (N = 1,289/14,105). Nominal P was 0.015/0.018 (fixed/random effect) for rs10994336 (Bonferroni corrected P = 0.044/0.053) and 0.023 for rs9804190 (Bonferroni corrected P = 0.069). None of the SNPs were significantly associated with SZ in the combined Nordic SZ case-control sample (N = 1,724/14,410). These results further support that ANK3 is a susceptibility gene specific to BD and that more than one risk locus is involved.
Subject(s)
Ankyrins/genetics , Bipolar Disorder/genetics , Genetic Association Studies , Schizophrenia/genetics , Case-Control Studies , Female , Gene Frequency , Genetic Predisposition to Disease , Genetic Variation , Genotype , Humans , Iceland , Male , Polymorphism, Single Nucleotide , Scandinavian and Nordic CountriesABSTRACT
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.
Subject(s)
Alzheimer Disease/genetics , Genetic Predisposition to Disease/genetics , Genome-Wide Association Study , Humans , Microglia/cytology , Multifactorial Inheritance/genetics , Polymorphism, Single Nucleotide/genetics , Proteins/metabolism , Proteolysis , Sample SizeABSTRACT
A recent genome-wide association study (GWAS) found significant association between the PALB2 SNP rs420259 and bipolar disorder (BD). The intracellular functions of the expressed proteins from the breast cancer risk genes PALB2 and BRCA2 are closely related. Therefore, we investigated the relation between genetic variants in PALB2 and BRCA2 and BD. Due to increasing evidence of genetic overlap between BD and schizophrenia (SCZ), we also investigated association with SCZ. In a Scandinavian case-control sample (n = 686/2,538) we found the BRCA2 SNP rs9567552 to be significantly associated with BD (Nominal P = 0.00043). Additionally, we replicated the association between PALB2 SNP rs420259 and BD (Nominal P = 0.025). We then combined our sample with another Nordic case-control sample (n = 435/11,491) from Iceland, and added results from the Wellcome Trust Case Control Consortium (WTCCC) (n = 1,868/2,938) and the STEP-UCL/ED-DUB-STEP2 study (n = 2,558/3,274) in a meta-analysis which revealed a P-value of 1.2 × 10(-5) for association between PALB2 SNP rs420259 and BD (n = 5,547/20,241). Neither the PALB2 SNP rs420259 nor the BRCA2 SNP rs9567552 were nominally significantly associated with the SCZ phenotype in our Scandinavian sample (n = 781/2,839). Our findings support PALB2 and BRCA2 as risk genes specifically for BD, and suggest that altered DNA repair related to neurogenesis may be involved in BD pathophysiology. © 2010 Wiley-Liss, Inc.