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- Jansen, I. E., et al.
(författare)
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Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:3, s. 404-413
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is highly heritable and recent studies have identified over 20 disease-associated genomic loci. Yet these only explain a small proportion of the genetic variance, indicating that undiscovered loci remain. Here, we performed a large genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 cases, 383,378 controls). AD-by-proxy, based on parental diagnoses, showed strong genetic correlation with AD (rg = 0.81). Meta-analysis identified 29 risk loci, implicating 215 potential causative genes. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver, and microglia). Gene-set analyses indicate biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomization results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD.
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- Witoelar, A, et al.
(författare)
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Meta-analysis of Alzheimer's disease on 9,751 samples from Norway and IGAP study identifies four risk loci
- 2018
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1, s. 18088-
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Tidskriftsartikel (refereegranskat)abstract
- A large fraction of genetic risk factors for Alzheimer’s Disease (AD) is still not identified, limiting the understanding of AD pathology and study of therapeutic targets. We conducted a genome-wide association study (GWAS) of AD cases and controls of European descent from the multi-center DemGene network across Norway and two independent European cohorts. In a two-stage process, we first performed a meta-analysis using GWAS results from 2,893 AD cases and 6,858 cognitively normal controls from Norway and 25,580 cases and 48,466 controls from the International Genomics of Alzheimer’s Project (IGAP), denoted the discovery sample. Second, we selected the top hits (p < 1 × 10−6) from the discovery analysis for replication in an Icelandic cohort consisting of 5,341 cases and 110,008 controls. We identified a novel genomic region with genome-wide significant association with AD on chromosome 4 (combined analysis OR = 1.07, p = 2.48 x 10-8). This finding implicated HS3ST1, a gene expressed throughout the brain particularly in the cerebellar cortex. In addition, we identified IGHV1-68 in the discovery sample, previously not associated with AD. We also associated USP6NL/ECHDC3 and BZRAP1-AS1 to AD, confirming findings from a follow-up transethnic study. These new gene loci provide further evidence for AD as a polygenic disorder, and suggest new mechanistic pathways that warrant further investigation.
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- Rongve, Arvid, et al.
(författare)
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GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study
- 2019
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Dementia with Lewy Bodies (DLB) is a common neurodegenerative disorder with poor prognosis and mainly unknown pathophysiology. Heritability estimates exceed 30% but few genetic risk variants have been identified. Here we investigated common genetic variants associated with DLB in a large European multisite sample. We performed a genome wide association study in Norwegian and European cohorts of 720 DLB cases and 6490 controls and included 19 top-associated single-nucleotide polymorphisms in an additional cohort of 108 DLB cases and 75545 controls from Iceland. Overall the study included 828 DLB cases and 82035 controls. Variants in the ASH1L/GBA (Chr1q22) and APOE ε4 (Chr19) loci were associated with DLB surpassing the genome-wide significance threshold (p < 5 × 10 −8 ). One additional genetic locus previously linked to psychosis in Alzheimer’s disease, ZFPM1 (Chr16q24.2), showed suggestive association with DLB at p-value < 1 × 10 −6 . We report two susceptibility loci for DLB at genome-wide significance, providing insight into etiological factors. These findings highlight the complex relationship between the genetic architecture of DLB and other neurodegenerative disorders.
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- Smeland, Olav B., et al.
(författare)
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Shared genetic variants between schizophrenia and general cognitive function indicate common molecular genetic mechanisms
- 2017
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Ingår i: European Neuropsychopharmacology. - : ELSEVIER SCIENCE BV. - 0924-977X .- 1873-7862. ; 27, s. S410-S410
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Schizophrenia (SCZ) is a severe mental disorder characterized by widespread cognitive impairments including deficits in learning, memory, processing speed, attention and executive functioning. Although cognitive deficits are a strong predictor of functional outcome in SCZ, current treatment strategies largely fail to ameliorate these impairments. Thus, in order to develop more efficient treatment strategies in SCZ, a better understanding of the pathogenesis of these cognitive deficits is needed. Given that both SCZ and cognitive ability are substantially heritable, we here aimed to determine whether SCZ share genetic influences with general cognitive function (COG), a phenotype that captures the shared variation in performance across several cognitive domains. Methods: We analyzed GWAS results in the form of summary statistics (p-values and z-scores) from SCZ (the Psychiatric Genomics Consortium; n=82 315) and COG (CHARGE Consortium; n=53 949). We applied a conditional false discovery rate (FDR) framework. By leveraging SNP-associations in a secondary trait (SCZ or COG), the conditional FDR approach increases power to detect loci in the primary trait (COG or SCZ), regardless of the directions of allelic effects of the risk loci. We then applied the conjunction FDR to identify shared loci between the phenotypes. The conjunction FDR is defined as the maximum of the conditional FDRs for both directions, and we used an overall FDR threshold of 0.05. Results: To visualize pleiotropic enrichment, we constructed conditional Q-Q plots which indicate substantial polygenetic overlap between SCZ and COG. For progressively stringent p-value thresholds for SCZ SNPs, we found approximately 150-fold enrichment for COG. For progressively stringent p-value thresholds for COG SNPs, we found approximately 100-fold enrichment for SCZ. We then used the conjunction FDR and identified fourteen independent loci shared between SCZ and COG. The majority of the shared loci show inverse associations in SCZ and COG, in line with the observed cognitive dysfunction in SCZ. Discussion: Our preliminary findings indicate shared molecular genetic mechanisms between SCZ and COG, which may provide important new insights into the pathogenesis of cognitive dysfunction in SCZ.
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- Zuber, V, et al.
(författare)
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Identification of shared genetic variants between schizophrenia and lung cancer
- 2018
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1, s. 674-
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Tidskriftsartikel (refereegranskat)abstract
- Epidemiology studies suggest associations between schizophrenia and cancer. However, the underlying genetic mechanisms are not well understood, and difficult to identify from epidemiological data. We investigated if there is a shared genetic architecture between schizophrenia and cancer, with the aim to identify specific overlapping genetic loci. First, we performed genome-wide enrichment analysis and second, we analyzed specific loci jointly associated with schizophrenia and cancer by the conjunction false discovery rate. We analyzed the largest genome-wide association studies of schizophrenia and lung, breast, prostate, ovary, and colon-rectum cancer including more than 220,000 subjects, and included genetic association with smoking behavior. Polygenic enrichment of associations with lung cancer was observed in schizophrenia, and weak enrichment for the remaining cancer sites. After excluding the major histocompatibility complex region, we identified three independent loci jointly associated with schizophrenia and lung cancer. The strongest association included nicotinic acetylcholine receptors and is an established pleiotropic locus shared between lung cancer and smoking. The two other loci were independent of genetic association with smoking. Functional analysis identified downstream pleiotropic effects on epigenetics and gene-expression in lung and brain tissue. These findings suggest that genetic factors may explain partly the observed epidemiological association of lung cancer and schizophrenia.
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