The Experts below are selected from a list of 8034 Experts worldwide ranked by ideXlab platform
Jose L Salazar - One of the best experts on this subject based on the ideXlab platform.
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Rare Functional Variant in tm2d3 is associated with late onset alzheimer s disease
PLOS Genetics, 2016Co-Authors: Johanna Jakobsdottir, Sven J Van Der Lee, Joshua C Bis, Vincent Chouraki, David Likroeger, Shinya Yamamoto, Megan L Grove, Adam C Naj, Maria Vronskaya, Jose L SalazarAbstract:We performed an exome-wide association analysis in 1393 late-onset Alzheimer’s disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a Rare Variant (P155L) in TM2D3 was enriched in Icelanders (~0.5% versus <0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES sub-study, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI) = 7.5 (3.5–15.9), p = 6.6x10-9]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a Functionally damaging allele. Our results establish a Rare TM2D3 Variant in association with LOAD susceptibility, and together with prior work suggests possible links to the β-amyloid cascade.
Lan Tan - One of the best experts on this subject based on the ideXlab platform.
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trem2 in alzheimer s disease
Molecular Neurobiology, 2013Co-Authors: Teng Jiang, Xi-chen Zhu, Lan TanAbstract:Recent works have demonstrated a Rare Functional Variant (R47H) in triggering receptor expressed on myeloid cells (TREM) 2 gene, encoding TREM2 protein, increase susceptibility to late-onset Alzheimer’s disease (AD), with an odds ratio similar to that of the apolipoprotein E e4 allele. The reduced function of TREM2 was speculated to be the main cause in the pathogenic effects of this risk Variant, and TREM2 is highly expressed in white matter, as well as in the hippocampus and neocortex, which is partly consistent with the pathological features reported in AD brain, indicating the possible involvement of TREM2 in AD pathogenesis. Emerging evidence has demonstrated that TREM2 could suppress inflammatory response by repression of microglia-mediated cytokine production and secretion, which may prevent inflammation-induced bystander damage of neurons. TREM2 also participates in the regulation of phagocytic pathways that are responsible for the removal of neuronal debris. In this article, we review the recent epidemiological findings of TREM2 that related with late-onset AD and speculate the possible roles of TREM2 in progression of this disease. Based on the potential protective actions of TREM2 in AD pathogenesis, targeting TREM2 might provide new opportunities for AD treatment.
Johanna Jakobsdottir - One of the best experts on this subject based on the ideXlab platform.
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Rare Functional Variant in tm2d3 is associated with late onset alzheimer s disease
PLOS Genetics, 2016Co-Authors: Johanna Jakobsdottir, Sven J Van Der Lee, Joshua C Bis, Vincent Chouraki, David Likroeger, Shinya Yamamoto, Megan L Grove, Adam C Naj, Maria Vronskaya, Jose L SalazarAbstract:We performed an exome-wide association analysis in 1393 late-onset Alzheimer’s disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a Rare Variant (P155L) in TM2D3 was enriched in Icelanders (~0.5% versus <0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES sub-study, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI) = 7.5 (3.5–15.9), p = 6.6x10-9]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a Functionally damaging allele. Our results establish a Rare TM2D3 Variant in association with LOAD susceptibility, and together with prior work suggests possible links to the β-amyloid cascade.
Kouichi Ozaki - One of the best experts on this subject based on the ideXlab platform.
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a Rare Functional Variant of sharpin attenuates the inflammatory response and associates with increased risk of late onset alzheimer s disease
Molecular Medicine, 2019Co-Authors: Yuya Asanomi, Daichi Shigemizu, Akinori Miyashita, Risa Mitsumori, Taiki Mori, Norikazu Hara, Kaoru Ito, Shumpei Niida, Takeshi Ikeuchi, Kouichi OzakiAbstract:Late-onset Alzheimer’s disease (LOAD), the most common form of dementia, results from complicated interactions among multiple environmental and genetic factors. Despite recent advances in genetic analysis of LOAD, more than half of the heritability for the disease remains unclear. Although genetic studies in Caucasians found Rare risk Variants for LOAD with large effect sizes, these Variants are hardly detectable in the Japanese population. To identify Rare Variants possibly explaining part of the genetic architecture for LOAD in Japanese people, we performed whole-exome sequencing analyses of 202 LOAD individuals without the APOE e4 risk allele, a major genetic factor for LOAD susceptibility. We also implemented in vitro Functional analyses of the Variant(s) to reveal possible functions associated with LOAD risk. Via step-by-step selection of whole-exome Variants, we found seven candidate risk Variants. We then conducted a case-control association study in a large Japanese cohort consisting of 4563 cases and 16,459 controls. We finally identified a Rare nonsynonymous Variant, rs572750141 (NM_030974.3:p.Gly186Arg), in SHARPIN that was potentially associated with increased risk of LOAD (corrected P = 8.05 × 10− 5, odds ratio = 6.1). The amino acid change in SHARPIN resulted in aberrant cellular localization of the Variant protein and attenuated the activation of NF-κB, a central mediator of inflammatory and immune responses. Our work identified a Rare Functional SHARPIN Variant as a previously unknown genetic risk factor for LOAD. The Functional alteration in SHARPIN induced by the Rare coding Variant is associated with an attenuated inflammatory/immune response that may promote LOAD development.
Richard Delorme - One of the best experts on this subject based on the ideXlab platform.
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No human tryptophan hydroxylase-2 gene R441H mutation in a large cohort of psychiatric patients and control subjects.
Biological Psychiatry, 2006Co-Authors: Richard Delorme, Christelle Durand, Catalina Betancur, Michael Wagner, Stephan Ruhrmann, Hans-juergen Grabe, Gudrun Nygren, Christopher Gillberg, Marion Leboyer, Thomas BourgeronAbstract:BACKGROUND: It was recently reported that a Rare Functional Variant, R441H, in the human tryptophan hydroxylase-2 gene (hTPH2) could represent an important risk factor for unipolar major depression (UP) since it was originally found in 10% of UP patients (vs. 1.4% in control subjects). METHODS: We explored the occurrence of this variation in patients with affective disorders (n = 646), autism spectrum disorders (n = 224), and obsessive-compulsive disorder (OCD) (n = 201); in healthy volunteers with no psychiatric disorders (n = 246); and in an ethnic panel of control individuals from North Africa, Sub-Saharan Africa, India, China, and Sweden (n = 277). RESULTS: Surprisingly, we did not observe the R441H Variant in any of the individuals screened (3188 independent chromosomes). CONCLUSIONS: Our results do not confirm the role of the R441H mutation of the hTPH2 gene in the susceptibility to UP. The absence of the Variant from a large cohort of psychiatric patients and control subjects suggests that the findings reported in the original study could be due to a genotyping error or to stratification of the initial population reported. Additional data by other groups should contribute to the clarification of the discrepancy between our results and those previous published.
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support for the association between the Rare Functional Variant i425v of the serotonin transporter gene and susceptibility to obsessive compulsive disorder
Molecular Psychiatry, 2005Co-Authors: Richard Delorme, Catalina Betancur, Michael Wagner, Gudrun Nygren, Marieodile Krebs, Philip Gorwood, Phillip L Pearl, Christelle M Durand, Friederike BuhtzAbstract:SIR—Recently, a Rare Functional Variant, I425V, in the serotonin transporter gene (SLC6A4) has been reported to be associated with a complex neuropsychiatric phenotype that includes obsessive-compulsive disorder (OCD), alcohol abuse/dependence, anorexia nervosa, and pervasive developmental disorder (PDD).1 Our study, performed in a large population of patients with these disorders, confirms the occurrence and the segregation of V425 in OCD. The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has been implicated in numerous psychiatric disorders, mostly because of the efficacy of serotonin reuptake inhibitors (SRIs). Among the polymorphisms identified in SLC6A4, three have been shown to be Functional. The Rare I425V variation, located in exon 9, increases the transport activity of the protein2, whereas the two more frequent polymorphisms, 5-HTTLPR located in the 5′-UTR of the gene, and STin2 located in intron 2, modify the transcriptional activity of the gene3,4. Despite a large number of studies, the Functional implications of the two frequent SLC6A4 polymorphisms in psychiatric disorders are still a matter of debate. In the present study, we sought to further explore the influence of the Rare but clearly Functional I425V Variant in a large sample of patients with OCD and other psychiatric conditions previously reported in the two families carrying I425V, i.e., FDD, anorexia nervosa, and alcohol abuse/dependence. To be included in the study, patients had to meet the DSM-IV criteria for OCD, anorexia nervosa, alcohol abuse/dependence, or FDD. The diagnosis of FDD was confirmed using the Autism Diagnostic Interview-Revised.5 For the other disorders, lifetime psychiatric evaluation was carried out using the Diagnostic Interview for Genetic Studies (DIGS)6 for adult patients, or the Kiddie Schedule for Affective Disorders and Schizophrenia for children.7 Healthy controls were included after being interviewed with the DIGS and the Family Interview for Genetic Studies8 to confirm the absence of both personal and family history of major psychiatric disorders. The local Research Ethics Boards reviewed and approved the study. The V425 was found in 3/254 probands with OCD, 1/284 with PDD, 1/124 with anorexia nervosa, in 1/285 healthy controls, but not in alcohol abusers/dependents (0/128) (Table 1). In OCD family 1, V425 was transmitted by the father who also had a lifetime history of OCD and single phobia. The paternal grandfather was alcoholic and tobacco dependant. No genotypic information was available for the paternal grandparents since the grandfather died of throat cancer and the grandmother of breast cancer. In OCD family 2, the mother and two siblings of the proband had committed suicide and the father was also dead, so no genotypic information was available for these individuals. OCD case 1 had only one brother, who committed suicide some years ago, so no genotypic information was available for him. No other clinical data were available concerning the first-degree relatives of OCD case 1. In FDD family 1, V425 was transmitted by the father and was present in the proband and two brothers. The father and one of the brothers carrying the V425 were both alcohol dependent. However, the youngest brother (19 years old), also carrying the V425 Variant, did not suffer from alcoholism or any other psychiatric disorder at the time of evaluation. Table 1 SCL6A4 genotypes and clinical features of the subjects included in the study Our results are in accordance with those previously reported by Ozaki et al1 on four points. First, we report a possibly higher occurrence of the V425 Variant in OCD compared to controls. Although the Variant is Rare, the combined results of the two studies indicate a significantly higher frequency of V425 in OCD compared to controls1,9 (5/457 vs. 2/884, Fisher exact test, P= 0.02). Second, despite the limited clinical and genotypic information on the families carrying the V425 Variant, our results suggest a possible co-segregation between the V425 and neuropsychiatric phenotypes, specifically in OCD. Third, Ozaki et al. hypothesized that the V425 Variant may confer treatment-resistance to SRIs. This was indirectly supported by our findings since all OCD probands carrying the V425 Variant in our study were considered resistant to SRIs, i.e., the severity of their obsessive and compulsive symptoms decreased less than 25% with multiple trials of a high dose of SRIs and a good compliance. Specifically, the three probands with OCD carrying the Variant showed poor or no response to multiple trials of SRIs at adequate doses over several years. Fourth, the analysis of the two additional polymorphisms of the SCL6A4 gene indicated that the V425 polymorphism might be associated with the L allele of 5-HTTLPR. However, our results do not confirm the hypothesis of a combined gain of function effect of both V425 and L/L genotype as a genetic risk for OCD, since this combined genotype was not present in all affected patients and, by contrast, was present in the control subject carrying the V425 Variant. In conclusion, our results are similar to those of the original report by Ozaki et al. and, therefore, lend support for a role of SLC6A4 V425 in the susceptibility to complex neuropsychiatric phenotypes. However, due to its global low frequency and to the fact that it was detected in a few controls, the role of V425 remains uncertain and should be interpreted with caution. We encourage other investigators, especially in the field of OCD, to screen for V425 in their samples. Indeed, the replication of these findings could ultimately implicate SLC6A4 as a true susceptibility gene to complex neuropsychiatric disorders, and consequently shed further light on the results obtained with the more frequent polymorphisms.
