| 1. |
- Blokland, G. A. M., et al.
(författare)
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Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders
- 2022
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Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 91:1, s. 102-117
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Tidskriftsartikel (refereegranskat)abstract
- Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. Results: Across disorders, genome-wide significant single nucleotide polymorphism–by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10−8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10−6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10−7; rs73033497, p = 8.8 × 10−7; rs7914279, p = 6.4 × 10−7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10−7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10−7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10−7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels. © 2021 Society of Biological Psychiatry
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| 3. |
- Mullins, N., et al.
(författare)
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Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology
- 2021
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 53, s. 817-829
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Tidskriftsartikel (refereegranskat)abstract
- Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies. Genome-wide association analyses of 41,917 bipolar disorder cases and 371,549 controls of European ancestry provide new insights into the etiology of this disorder and identify novel therapeutic leads and potential opportunities for drug repurposing.
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| 8. |
- Bonham, LW, et al.
(författare)
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Genetic variation across RNA metabolism and cell death gene networks is implicated in the semantic variant of primary progressive aphasia
- 2019
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 10854-
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Tidskriftsartikel (refereegranskat)abstract
- The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by neurodegeneration and progressive loss of semantic knowledge. Unlike many other forms of frontotemporal lobar degeneration (FTLD), svPPA has a highly consistent underlying pathology composed of TDP-43 (a regulator of RNA and DNA transcription metabolism). Previous genetic studies of svPPA are limited by small sample sizes and a paucity of common risk variants. Despite this, svPPA’s relatively homogenous clinicopathologic phenotype makes it an ideal investigative model to examine genetic processes that may drive neurodegenerative disease. In this study, we used GWAS metadata, tissue samples from pathologically confirmed frontotemporal lobar degeneration, and in silico techniques to identify and characterize protein interaction networks associated with svPPA risk. We identified 64 svPPA risk genes that interact at the protein level. The protein pathways represented in this svPPA gene network are critical regulators of RNA metabolism and cell death, such as SMAD proteins and NOTCH1. Many of the genes in this network are involved in TDP-43 metabolism. Contrary to the conventional notion that svPPA is a clinical syndrome with few genetic risk factors, our analyses show that svPPA risk is complex and polygenic in nature. Risk for svPPA is likely driven by multiple common variants in genes interacting with TDP-43, along with cell death,x` working in combination to promote neurodegeneration.
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| 14. |
- Gao, YX, et al.
(författare)
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Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis
- 2020
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1, s. 12184-
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Tidskriftsartikel (refereegranskat)abstract
- We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93–1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53–1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population.
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| 16. |
- Albani, D, et al.
(författare)
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Insulin-like growth factor 1 receptor polymorphism rs2229765 and circulating interleukin-6 level affect male longevity in a population-based prospective study (Treviso Longeva--TRELONG).
- 2011
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Ingår i: The Aging Male. - 1368-5538. ; 14:4, s. 257-264
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Tidskriftsartikel (refereegranskat)abstract
- Insulin-like growth factor 1 (IGF-1) signaling modulation has been associated with increased lifespan in model organisms, while high levels of circulating interleukin-6 (IL-6) are a marker of disability and mortality. In the prospective, population-based "Treviso Longeva"--TRELONG Study from Italy (n = 668, age range 70-105.5 years at baseline, followed for seven years) we investigated the effects of survival on the IGF-1 receptor (IGF-1R) gene polymorphism rs2229765, the IL-6 gene promoter polymorphism rs1800795, and plasma concentrations of IGF-1 and IL-6, alone or in combination. We found a sex-dependent effect for the IGF-1R rs2229765 polymorphism, as male carriers of the homozygous A/A genotype survived longer, while the IL-6 rs1800795 genotype did not influence overall or sex-specific longevity. Higher IL-6 levels were more detrimental for survival among males than females, while IGF-1 had no dose-response effect. These findings sustain the hypothesis that sex-specific longevity relies on detectable differences in genetic and biochemical parameters between males and females.
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| 21. |
- Albani, S, et al.
(författare)
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Twelve thousand years of dust : the Holocene global dust cycle constrained by natural archives
- 2015
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Ingår i: Climate of the Past. - : Copernicus GmbH. - 1814-9324 .- 1814-9332. ; 11:6, s. 869-903
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Tidskriftsartikel (refereegranskat)abstract
- Mineral dust plays an important role in the climate system by interacting with radiation, clouds, and biogeochemical cycles. In addition, natural archives show that the dust cycle experienced variability in the past in response to global and local climate change. The compilation of the DIRTMAP paleodust datasets in the last two decades provided a target for paleoclimate models that include the dust cycle, following a time slice approach. We propose an innovative framework to organize a paleodust dataset that moves on from the positive experience of DIRTMAP and takes into account new scientific challenges, by providing a concise and accessible dataset of temporally resolved records of dust mass accumulation rates and particle grain-size distributions. We consider data from ice cores, marine sediments, loess/paleosol sequences, lake sediments, and peat bogs for this compilation, with a temporal focus on the Holocene period. This global compilation allows investigation of the potential, uncertainties and confidence level of dust mass accumulation rates reconstructions, and highlights the importance of dust particle size information for accurate and quantitative reconstructions of the dust cycle. After applying criteria that help to establish that the data considered represent changes in dust deposition, 43 paleodust records have been identified, with the highest density of dust deposition data occurring in the North Atlantic region. Although the temporal evolution of dust in the North Atlantic appears consistent across several cores and suggest that minimum dust fluxes are likely observed during the Early to mid-Holocene period (6000–8000 years ago), the magnitude of dust fluxes in these observations is not fully consistent, suggesting that more work needs to be done to synthesize datasets for the Holocene. Based on the data compilation, we used the Community Earth System Model to estimate the mass balance and variability of the global dust cycle during the Holocene, with dust load ranging from 17.1 to 20.5 Tg between 2000 and 10 000 years ago, and a minimum in the Early to Mid-Holocene (6000–8000 years ago).
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| 23. |
- Gallucci, M, et al.
(författare)
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Factors related to disability: Evidence from the "Treviso Longeva (TRELONG) Study"
- 2010
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Ingår i: Archives of gerontology and geriatrics. - : Elsevier BV. - 1872-6976 .- 0167-4943. ; 52:3, s. 309-16
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Tidskriftsartikel (refereegranskat)abstract
- Prolongation of life is an important public health goal as long as there is an emphasis on the quality of life (QoL) and independent living. Diminishing abilities to ambulate and participate in activities of daily living point to a serious decline in functional health, increasing the risk of institutionalization and death. In our work we found a pattern of factors associated with disability, especially cognitive impairment, as well as stroke, physical activity and performance, reading, and the nutritional biomarkers, blood albumin and high-density lipoprotein cholesterol (HDL-C). The attention to this cluster of markers, suggesting multidimensional prevention, may have unexpected good effects against disability.
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| 24. |
- Gustafson, Deborah, 1966, et al.
(författare)
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Body Mass Index, Cognition, Disability, APOE Genotype, and Mortality: The "Treviso Longeva" Study
- 2012
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Ingår i: American Journal of Geriatric Psychiatry. - 1064-7481. ; 20:7, s. 594-602
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The concurrent contributions of dynamic, interrelated late-life parameters, such as bodymass index (BMI), cognition, and physical functioning on mortality in the elderly are unclear, as is the influence of APOE genotype. We explored these measures in relation to 7-year mortality in long-lived Italian elderly. Design: A representative, age-stratified, population sample. Setting: The Treviso Longeva (TRELONG) Study, in Treviso, Italy. Participants: Three hundred eleven men and 357 women, aged 70 years and older (mean age 84 +/- 8 years). Measurements: Seven-year mortality, BMI, Mini-Mental State Examination (MMSE) score, Activities of Daily Living (ADL), APOE genotype, and a variety of clinical and survey data. Results: In separate age-and sex-adjusted analyses, BMI <18.5 kg/m(2), MMSE <= 24, and ADL <6, were associated with greater 7-year mortality among adults aged 70 years and older. In a multivariate model including all factors, MMSE <= 24, and ADL <6 were associated with greater mortality; BMI >= 30 kg/m(2) was protective. There were no interactions between BMI, MMSE, or ADL. When excluding those dying within 3 years of baseline, only an MMSE <= 24 was related to mortality. APOE epsilon 4 was not related to mortality. Conclusion: Higher MMSE score, higher ADL score, and higher BMI, independent of age, sex, and other factors, are markers for longer life among northern Italian adults aged 70 years or older. Global cognition, BMI, and physical functioning, assessed by short, simple tests are profound indicators of death within less than a decade. (Am J Geriatr Psychiatry 2012; 20:594-602)
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