| 1. |
- Hou, Liping, et al.
(författare)
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Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder.
- 2016
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Ingår i: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 25:15, s. 3383-94
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Tidskriftsartikel (refereegranskat)abstract
- Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behavior. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ∼2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, p=5.87×10(-9); odds ratio=1.12) and markers within ERBB2 (rs2517959, p=4.53×10(-9); odds ratio=1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.
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| 2. |
- Jones, Lesley, et al.
(författare)
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Convergent genetic and expression data implicate immunity in Alzheimer's disease
- 2015
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 11:6, s. 658-671
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Tidskriftsartikel (refereegranskat)abstract
- Background: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. Methods: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 X 10(-12) after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 X 10(-11)), cholesterol transport (P = 2.96 X 10(-9)), and proteasome-ubiquitin activity (P = 1.34 X 10(-6)). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05). Conclusions: The immime response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.
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| 3. |
- Kalman, Janos L, et al.
(författare)
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Investigating polygenic burden in age at disease onset in bipolar disorder: Findings from an international multicentric study.
- 2019
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Ingår i: Bipolar disorders. - : Wiley. - 1399-5618 .- 1398-5647. ; 21:1, s. 68-75
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Tidskriftsartikel (refereegranskat)abstract
- Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early-onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD- and schizophrenia (SCZ)-associated risk variants is associated with an earlier AAO in BD patients.A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn-Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18years] vs adulthood [>18years]) or considered as a continuous measure. The associations between BD- and SCZ-PRSs and AAO were evaluated with regression models.BD- and SCZ-PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment.The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype.
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| 4. |
- Amare, Azmeraw T, et al.
(författare)
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Association of Polygenic Score for Schizophrenia and HLA Antigen and Inflammation Genes With Response to Lithium in Bipolar Affective Disorder: A Genome-Wide Association Study.
- 2018
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Ingår i: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 75:1, s. 65-74
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Tidskriftsartikel (refereegranskat)abstract
- Lithium is a first-line mood stabilizer for the treatment of bipolar affective disorder (BPAD). However, the efficacy of lithium varies widely, with a nonresponse rate of up to 30%. Biological response markers are lacking. Genetic factors are thought to mediate treatment response to lithium, and there is a previously reported genetic overlap between BPAD and schizophrenia (SCZ).To test whether a polygenic score for SCZ is associated with treatment response to lithium in BPAD and to explore the potential molecular underpinnings of this association.A total of 2586 patients with BPAD who had undergone lithium treatment were genotyped and assessed for long-term response to treatment between 2008 and 2013. Weighted SCZ polygenic scores were computed at different P value thresholds using summary statistics from an international multicenter genome-wide association study (GWAS) of 36989 individuals with SCZ and genotype data from patients with BPAD from the Consortium on Lithium Genetics. For functional exploration, a cross-trait meta-GWAS and pathway analysis was performed, combining GWAS summary statistics on SCZ and response to treatment with lithium. Data analysis was performed from September 2016 to February 2017.Treatment response to lithium was defined on both the categorical and continuous scales using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. The effect measures include odds ratios and the proportion of variance explained.Of the 2586 patients in the study (mean [SD] age, 47.2 [13.9] years), 1478 were women and 1108 were men. The polygenic score for SCZ was inversely associated with lithium treatment response in the categorical outcome, at a threshold P<5×10-2. Patients with BPAD who had a low polygenic load for SCZ responded better to lithium, with odds ratios for lithium response ranging from 3.46 (95% CI, 1.42-8.41) at the first decile to 2.03 (95% CI, 0.86-4.81) at the ninth decile, compared with the patients in the 10th decile of SCZ risk. In the cross-trait meta-GWAS, 15 genetic loci that may have overlapping effects on lithium treatment response and susceptibility to SCZ were identified. Functional pathway and network analysis of these loci point to the HLA antigen complex and inflammatory cytokines.This study provides evidence for a negative association between high genetic loading for SCZ and poor response to lithium in patients with BPAD. These results suggest the potential for translational research aimed at personalized prescribing of lithium.
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| 5. |
- Bauer, Michael, et al.
(författare)
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Association between solar insolation and a history of suicide attempts in bipolar I disorder.
- 2019
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Ingår i: Journal of psychiatric research. - : Elsevier BV. - 1879-1379 .- 0022-3956. ; 113, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- In many international studies, rates of completed suicide and suicide attempts have a seasonal pattern that peaks in spring or summer. This exploratory study investigated the association between solar insolation and a history of suicide attempt in patients with bipolar I disorder. Solar insolation is the amount of electromagnetic energy from the Sun striking a surface area on Earth. Data were collected previously from 5536 patients with bipolar I disorder at 50 collection sites in 32 countries at a wide range of latitudes in both hemispheres. Suicide related data were available for 3365 patients from 310 onset locations in 51 countries. 1047 (31.1%) had a history of suicide attempt. There was a significant inverse association between a history of suicide attempt and the ratio of mean winter solar insolation/mean summer solar insolation. This ratio is smallest near the poles where the winter insolation is very small compared to the summer insolation. This ratio is largest near the equator where there is relatively little variation in the insolation over the year. Other variables in the model that were positively associated with suicide attempt were being female, a history of alcohol or substance abuse, and being in a younger birth cohort. Living in a country with a state-sponsored religion decreased the association. (All estimated coefficients p<0.01). In summary, living in locations with large changes in solar insolation between winter and summer may be associated with increased suicide attempts in patients with bipolar disorder. Further investigation of the impacts of solar insolation on the course of bipolar disorder is needed.
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| 6. |
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| 7. |
- Pisanu, Claudia, et al.
(författare)
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Evidence that genes involved in hedgehog signaling are associated with both bipolar disorder and high BMI
- 2019
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Ingår i: Translational Psychiatry. - : NATURE PUBLISHING GROUP. - 2158-3188. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Patients with bipolar disorder (BD) show higher frequency of obesity and type 2 diabetes (T2D), but the underlying genetic determinants and molecular pathways are not well studied. Using large publicly available datasets, we (1) conducted a gene-based analysis using MAGMA to identify genes associated with BD and body mass index (BMI) or T2D and investigated their functional enrichment; and (2) performed two meta-analyses between BD and BMI, as well as BD and T2D using Metasoft. Target druggability was assessed using the Drug Gene Interaction Database (DGIdb). We identified 518 and 390 genes significantly associated with BD and BMI or BD and T2D, respectively. A total of 52 and 12 genes, respectively, were significant after multiple testing correction. Pathway analyses conducted on nominally significant targets showed that genes associated with BD and BMI were enriched for the Neuronal cell body Gene Ontology (GO) term (p = 1.0E-04; false discovery rate (FDR) = 0.025) and different pathways, including the Signaling by Hedgehog pathway (p = 4.8E -05, FDR = 0.02), while genes associated with BD and T2D showed no specific enrichment. The meta-analysis between BD and BMI identified 64 relevant single nucleotide polymorphisms (SNPs). While the majority of these were located in intergenic regions or in a locus on chromosome 16 near and in the NPIPL1 and SH2B1 genes (best SNP: rs4788101, p = 2.1E-24), five were located in the ETV5 gene (best SNP: rs1516725, p= 1E-24), which was previously associated with both BD and obesity, and one in the RPGRIP1L gene (rs1477199, p = 5.7E-09), which was also included in the Signaling by Hedgehog pathway. The meta-analysis between BD and T2D identified six significant SNPs, three of which were located in ALAS1 (best SNP: rs352165, p = 3.4E-08). Thirteen SNPs associated with BD and BMI, and one with BD and T2D, were located in genes which are part of the druggable genome. Our results support the hypothesis of shared genetic determinants between BD and BMI and point to genes involved in Hedgehog signaling as promising targets.
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| 8. |
- Pisanu, Claudia, et al.
(författare)
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A genetic risk score is differentially associated with migraine with and without aura
- 2017
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Ingår i: Human Genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 136:8, s. 999-1008
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Tidskriftsartikel (refereegranskat)abstract
- Although a number of migraine-associated single-nucleotide polymorphisms (SNP) with small effect size have been identified, little is known about the additive impact of these variants on migraine risk, frequency and severity. We investigated to what extent a genetic risk score (GRS) based on recently published, novel migraine-associated SNPs is associated with migraine prevalence, subtypes and severity in a large population-based sample. The sample comprised 446 subjects with migraine and 2511 controls from the CoLaus/PsyCoLaus study. Fifty-four SNPs earlier associated with migraine were selected. SNPs with a low impact on migraine prevalence in our sample were excluded using random forest. We combined the remaining 21 SNPs into a GRS and analyzed the association with migraine using logistic regression models. The GRS was significantly associated with migraine (OR = 1.56, p = 0.02) and migraine without aura (MWOA) (OR = 2.01, p = 0.003), but not with migraine with aura (MWA). The GRS was not associated with migraine frequency, intensity or interference with daily activities. We show that a GRS combining multiple genetic risk variants is associated with MWOA but not MWA, suggesting a different genetic susceptibility background underlying the two forms of migraine.
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| 9. |
- Pisanu, Claudia, et al.
(författare)
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High leptin levels are associated with migraine with aura
- 2017
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Ingår i: Cephalalgia. - : SAGE Publications. - 0333-1024 .- 1468-2982. ; 37:5, s. 435-441
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Migraine is a prevalent disorder characterised by recurrent headache attacks preceded or accompanied by aura in a subgroup of patients. Migraine often occurs together with major depressive disorder (MDD). Alterations of adipokine levels have been reported both in migraine and in MDD. In this cross-sectional study, we aimed to assess the associations between serum leptin and adiponectin levels and migraine or migraine subtypes. Analyses were adjusted for a lifetime history of MDD in order to investigate the association between adipokines and migraine under consideration of depression status.METHODS: We included 3025 participants from the CoLaus/PsyCoLaus study. The impact of leptin and adiponectin levels on a diagnosis of migraine was analysed by binary regression analyses, adjusting for variables known to influence adipokine levels. Subgroup analyses were conducted based on the presence of aura.RESULTS: Crude leptin levels were significantly higher in subjects with migraine than controls (Mann-Whitney U = 515,102, p = 6 × 10(-7)). When performing adjusted analyses, leptin levels were found to be significantly higher in subjects with migraine (odds ratio = 1.22, p = 0.024) and migraine with aura (odds ratio = 1.34, p = 0.004).CONCLUSION: High leptin levels might play a role in the pathogenesis of migraine and migraine with aura.
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