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- Dalmasso, MC, et al.
(author)
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Transethnic meta-analysis of rare coding variants in PLCG2, ABI3, and TREM2 supports their general contribution to Alzheimer's disease
- 2019
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In: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 9:1, s. 55-
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Journal article (peer-reviewed)abstract
- Rare coding variants in TREM2, PLCG2, and ABI3 were recently associated with the susceptibility to Alzheimer’s disease (AD) in Caucasians. Frequencies and AD-associated effects of variants differ across ethnicities. To start filling the gap on AD genetics in South America and assess the impact of these variants across ethnicity, we studied these variants in Argentinian population in association with ancestry. TREM2 (rs143332484 and rs75932628), PLCG2 (rs72824905), and ABI3 (rs616338) were genotyped in 419 AD cases and 486 controls. Meta-analysis with European population was performed. Ancestry was estimated from genome-wide genotyping results. All variants show similar frequencies and odds ratios to those previously reported. Their association with AD reach statistical significance by meta-analysis. Although the Argentinian population is an admixture, variant carriers presented mainly Caucasian ancestry. Rare coding variants in TREM2, PLCG2, and ABI3 also modulate susceptibility to AD in populations from Argentina, and they may have a European heritage.
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- Kurth, F, et al.
(author)
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Large-scale analysis of structural brain asymmetries during neurodevelopment : Associations with age and sex in 4265 children and adolescents.
- 2024
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In: Human Brain Mapping. - 1065-9471 .- 1097-0193. ; 45:11, s. e26754-
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Journal article (peer-reviewed)abstract
- Only a small number of studies have assessed structural differences between the two hemispheres during childhood and adolescence. However, the existing findings lack consistency or are restricted to a particular brain region, a specific brain feature, or a relatively narrow age range. Here, we investigated associations between brain asymmetry and age as well as sex in one of the largest pediatric samples to date (n = 4265), aged 1-18 years, scanned at 69 sites participating in the ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) consortium. Our study revealed that significant brain asymmetries already exist in childhood, but their magnitude and direction depend on the brain region examined and the morphometric measurement used (cortical volume or thickness, regional surface area, or subcortical volume). With respect to effects of age, some asymmetries became weaker over time while others became stronger; sometimes they even reversed direction. With respect to sex differences, the total number of regions exhibiting significant asymmetries was larger in females than in males, while the total number of measurements indicating significant asymmetries was larger in males (as we obtained more than one measurement per cortical region). The magnitude of the significant asymmetries was also greater in males. However, effect sizes for both age effects and sex differences were small. Taken together, these findings suggest that cerebral asymmetries are an inherent organizational pattern of the brain that manifests early in life. Overall, brain asymmetry appears to be relatively stable throughout childhood and adolescence, with some differential effects in males and females.
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- Lambert, J-C, et al.
(author)
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Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease
- 2013
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In: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 18:4, s. 461-470
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Journal article (peer-reviewed)abstract
- Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimer's disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome-wide haplotype association (GWHA) study in the EADI1 study (n = 2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case-control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43-1.96); P=1.1 x 10(-10)). We finally searched for association between SNPs within the FRMD4A locus and A beta plasma concentrations in three independent non-demented populations (n = 2579). We reported that polymorphisms were associated with plasma A beta 42/A beta 40 ratio (best signal, P=5.4 x 10(-7)). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD.
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- George, Julie, et al.
(author)
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Comprehensive genomic profiles of small cell lung cancer
- 2015
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 524:7563, s. 47-U73
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Journal article (peer-reviewed)abstract
- We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Dex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.
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- Helsmoortel, Celine, et al.
(author)
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A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP
- 2014
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46:4, s. 380-
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Journal article (peer-reviewed)abstract
- Despite the high heritability of autism spectrum disorders (ASD), characterized by persistent deficits in social communication and interaction and restricted, repetitive patterns of behavior, interests or activities(1), a genetic diagnosis can be established in only a minority of patients. Known genetic causes include chromosomal aberrations, such as the duplication of the 15q11-13 region, and monogenic causes, as in Rett and fragile- X syndromes. The genetic heterogeneity within ASD is striking, with even the most frequent causes responsible for only 1% of cases at the most. Even with the recent developments in nextgeneration sequencing, for the large majority of cases no molecular diagnosis can be established(2-7). Here, we report ten patients with ASD and other shared clinical characteristics, including intellectual disability and facial dysmorphisms caused by a mutation in ADNP, a transcription factor involved in the SWI/ SNF remodeling complex. We estimate this gene to be mutated in at least 0.17% of ASD cases, making it one of the most frequent ASD- associated genes known to date.
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- Islar, Mine, et al.
(author)
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Diverse values of nature for sustainability
- 2022
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In: Nature. - 0028-0836 .- 1476-4687. ; 620, s. 813-823
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Journal article (peer-reviewed)abstract
- Twenty-five years since foundational publications on valuing ecosystem services for human well-being1,2, addressing the global biodiversity crisis3 still implies confronting barriers to incorporating nature’s diverse values into decision-making. These barriers include powerful interests supported by current norms and legal rules such as property rights, which determine whose values and which values of nature are acted on. A better understanding of how and why nature is (under)valued is more urgent than ever4. Notwithstanding agreements to incorporate nature’s values into actions, including the Kunming-Montreal Global Biodiversity Framework (GBF)5 and the UN Sustainable Development Goals6, predominant environmental and development policies still prioritize a subset of values, particularly those linked to markets, and ignore other ways people relate to and benefit from nature7. Arguably, a ‘values crisis’ underpins the intertwined crises of biodiversity loss and climate change8, pandemic emergence9 and socio-environmental injustices10. On the basis of more than 50,000 scientific publications, policy documents and Indigenous and local knowledge sources, the Intergovernmental Platform on Biodiversity and Ecosystem Services (IPBES) assessed knowledge on nature’s diverse values and valuation methods to gain insights into their role in policymaking and fuller integration into decisions7,11. Applying this evidence, combinations of values-centred approaches are proposed to improve valuation and address barriers to uptake, ultimately leveraging transformative changes towards more just (that is, fair treatment of people and nature, including inter- and intragenerational equity) and sustainable futures.
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- Ssekamatte, Tonny, et al.
(author)
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Do sexual expectancies and inhibitions predict high-risk sexual behaviours? Evidence from a cross-sectional survey among young psychoactive substance users in informal settlements in Kampala, Uganda
- 2021
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In: BMC Public Health. - : BioMed Central. - 1471-2458. ; 21:1
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Journal article (peer-reviewed)abstract
- Background: Psychoactive substance use is a public health challenge among young people in informal settlements. Though rarely examined, psychoactive substance use is linked to sexual expectancies and inhibitions, and consequently high-risk sexual behaviours. This study examined the association between sexual expectancies and inhibitions, and high-risk sexual behaviours among young psychoactive substance users (PSUs) in informal settlements in Kampala, Uganda.Methods: This cross-sectional study recruited 744 young PSUs from informal settlements in Kampala. Respondent driven sampling was used to recruit respondents. A ‘modified’ Poisson regression model was used for inferential statistics. Data were analysed using the Stata 14 software.Results: Of the 744 study participants, 45.6% believed that psychoactive substance use improves sexual performance; 43.3% believed that psychoactive substances make sex more pleasurable, and 53.3% believed that psychoactive substances give courage or confidence to approach a partner for sex. The belief that psychoactive substance use improves sexual performance (PR 1.14, 95% CI: 1.01–1.30), increases the likelihood of engaging in sex (PR 1.20, 95% CI: 1.04–1.40) or gives courage or confidence to approach a sexual partner (PR 1.21, 95% CI: 1.05–1.39) were associated with having sex while under the influence of psychoactive substances. The belief that a psychoactive substance user under the influence of psychoactive substances is more likely to engage in sex (PR 1.48, 95% CI: 1.15–1.90), and likely to find it difficult to refuse sex (PR 1.28, 95% CI: 1.06–1.55) were positively associated with engaging in multiple sexual partnerships. The belief that one easily forgets to use a condom when under the influence of psychoactive substances was positively associated with inconsistent condom use (PR 1.26, 95% CI: 1.09–1.45).Conclusion: Psychoactive substance use expectancies associated with high-risk sexual behaviours included the belief that psychoactive substances improve sexual performance and improve confidence in approaching a sexual partner. Psychoactive substance use inhibitions associated with high-risk sexual behaviours included an increased likelihood of engaging in sexual intercourse, difficulties in refusing to engage in sexual intercourse, and forgetting to use condoms while intoxicated. Interventions targeting a reduction in high-risk sexual behaviour should integrate the impact of psychoactive substance use on sexual behaviour.
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| 25. |
- Ssekamatte, Tonny, et al.
(author)
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Multiple sexual partnerships and associated factors among young psychoactive-substance-users in informal settlements in Kampala, Uganda
- 2020
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In: PLOS ONE. - : Public Library Science. - 1932-6203. ; 15:10
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Journal article (peer-reviewed)abstract
- Background: Multiple sexual partnerships increase the risk of transmission of HIV and can be exacerbated by substance abuse. However, the association between psychoactive substance use and multiple sexual partnerships among young people in informal settlements of low-income countries is not well known. This study established the prevalence of multiple sexual partnerships and associated factors among young psychoactive-substance-users in informal settlements in Kampala, Uganda.Methods: This was a cross-sectional study involving 744 young (aged 18-24 years), sexually active, psychoactive substance-users selected from 12 of the 57 informal settlements of Kampala City. The prevalence of multiple sexual partnerships and their differential distribution by socio-demographic strata was established. Modified Poisson regression models were run in Stata 14 software to generate prevalence rate ratios for the factors associated with multiple sexual partnerships.Results: About 40.6% (37.9% of males and 50.0% of females) had engaged in multiple sexual partnerships in the last 30 days. Engaging in multiple sexual partnerships in the last 30 days was positively associated with being female (PR 1.29, 95% CI: 1.03-1.63); staying in the informal settlement for 6-10 years (PR 1.34, 95% CI: 1.02-1.75) and chewing khat in the last 30 days (PR 1.93, 95% CI: 1.10-3.40).Conclusion: Multiple sexual partnerships are highly prevalent among young psychoactive-substance-users, irrespective of the socio-demographic strata. Being female, having lived in the informal settlement for 6-10 years, and chewing khat were significantly associated with having multiple sexual partners in the last 30 days. In tackling this high-risk sexual behaviour, it is recommended that risk-reduction interventions are considered for the different socio-demographic strata identified in this study, i.e. females, those who have lived in the informal settlement for about 6-10 years, and those who chew khat.
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| 26. |
- Venkatesan, Meera, et al.
(author)
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Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes : parasite risk factors that affect treatment outcomes for P. falciparum malaria after artemether-lumefantrine and artesunate-amodiaquine.
- 2014
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In: The American journal of tropical medicine and hygiene. - : American Society of Tropical Medicine and Hygiene. - 1476-1645 .- 0002-9637. ; 91:4, s. 833-43
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Journal article (peer-reviewed)abstract
- Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network. Data for more than 7,000 patients were analyzed to assess relationships between parasite polymorphisms in pfcrt and pfmdr1 and clinically relevant outcomes after treatment with AL or ASAQ. Presence of the pfmdr1 gene N86 (adjusted hazards ratio = 4.74, 95% confidence interval = 2.29 - 9.78, P < 0.001) and increased pfmdr1 copy number (adjusted hazards ratio = 6.52, 95% confidence interval = 2.36-17.97, P < 0.001 : were significant independent risk factors for recrudescence in patients treated with AL. AL and ASAQ exerted opposing selective effects on single-nucleotide polymorphisms in pfcrt and pfmdr1. Monitoring selection and responding to emerging signs of drug resistance are critical tools for preserving efficacy of artemisinin combination therapies; determination of the prevalence of at least pfcrt K76T and pfmdr1 N86Y should now be routine.
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