ORCID Profile
0000-0001-7415-7607
Current Organisation
Dalhousie University
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Publisher: Springer Science and Business Media LLC
Date: 27-10-2013
DOI: 10.1038/NG.2802
Publisher: Research Square Platform LLC
Date: 26-06-2023
DOI: 10.21203/RS.3.RS-3068352/V1
Abstract: The link between bipolar disorder (BP) and immune dysfunction remains controversial. While epidemiological studies have long suggested an association, recent research has found only limited evidence of such a relationship. To clarify this, we investigated the contributions of immune-relevant genetic factors to the response to lithium (Li) treatment and the clinical presentation of BP. First, we assessed the association of a large collection of immune-related genes (4,925) with Li response, defined by the Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale), and clinical characteristics in patients with BP from the International Consortium on Lithium Genetics (ConLi + Gen, N = 2,374). Second, we calculated here previously published polygenic scores (PGSs) for immune-related traits and evaluated their associations with Li response and clinical features. We found several genes associated with Li response at p 1x10 − 4 values, including HAS3 , CNTNAP5 and NFIB . Network and functional enrichment analyses uncovered an overrepresentation of pathways involved in cell adhesion and intercellular communication, which appear to converge on the well-known Li-induced inhibition of GSK-3β. We also found various genes associated with BP’s age-at-onset, number of mood episodes, and presence of psychosis, substance abuse and/or suicidal ideation at the exploratory threshold. These included RTN4 , XKR4 , NRXN1 , NRG1/3 and GRK5 . Additionally, PGS analyses suggested serum FAS, ECP, TRANCE and cytokine ligands, amongst others, might represent potential circulating biomarkers of Li response and clinical presentation. Taken together, our results support the notion of a relatively weak association between immunity and clinically relevant features of BP at the genetic level.
Publisher: Oxford University Press (OUP)
Date: 21-06-2016
DOI: 10.1093/HMG/DDW181
Publisher: Elsevier BV
Date: 03-2016
Publisher: Springer Science and Business Media LLC
Date: 16-03-2200
DOI: 10.1038/S41380-020-0689-5
Abstract: Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLi
Publisher: Springer Science and Business Media LLC
Date: 07-06-2021
DOI: 10.1038/S41467-021-22491-8
Abstract: Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select in iduals at high risk of Alzheimer’s disease.
Publisher: Springer Science and Business Media LLC
Date: 11-07-2022
Publisher: Elsevier BV
Date: 10-2022
Publisher: Springer Science and Business Media LLC
Date: 09-02-2023
Publisher: Springer Science and Business Media LLC
Date: 29-11-2021
DOI: 10.1038/S41398-021-01702-2
Abstract: Lithium is the gold standard therapy for Bipolar Disorder (BD) but its effectiveness differs widely between in iduals. The molecular mechanisms underlying treatment response heterogeneity are not well understood, and personalized treatment in BD remains elusive. Genetic analyses of the lithium treatment response phenotype may generate novel molecular insights into lithium’s therapeutic mechanisms and lead to testable hypotheses to improve BD management and outcomes. We used fixed effect meta-analysis techniques to develop meta-analytic polygenic risk scores (MET-PRS) from combinations of highly correlated psychiatric traits, namely schizophrenia (SCZ), major depression (MD) and bipolar disorder (BD). We compared the effects of cross-disorder MET-PRS and single genetic trait PRS on lithium response. For the PRS analyses, we included clinical data on lithium treatment response and genetic information for n = 2283 BD cases from the International Consortium on Lithium Genetics (ConLi + Gen www.ConLiGen.org ). Higher SCZ and MD PRSs were associated with poorer lithium treatment response whereas BD-PRS had no association with treatment outcome. The combined MET2-PRS comprising of SCZ and MD variants (MET2-PRS) and a model using SCZ and MD-PRS sequentially improved response prediction, compared to single-disorder PRS or to a combined score using all three traits (MET3-PRS). Patients in the highest decile for MET2-PRS loading had 2.5 times higher odds of being classified as poor responders than patients with the lowest decile MET2-PRS scores. An exploratory functional pathway analysis of top MET2-PRS variants was conducted. Findings may inform the development of future testing strategies for personalized lithium prescribing in BD.
Publisher: Wiley
Date: 22-01-2013
DOI: 10.1002/AJMG.B.32132
Publisher: Cold Spring Harbor Laboratory
Date: 28-08-2023
DOI: 10.1101/2023.08.26.23294659
Abstract: A significant proportion of patients with major depressive disorder (MDD) do not experience remission after one or more pharmacological treatments. Research has explored brain structural measures, particularly the hippoc us, as potential predictors of treatment response in MDD, as well as genetic factors. This study investigated the association of polygenic scores (PGSs) for seven subcortical brain volumes (including the hippoc us, nucleus accumbens, amygdala, and caudate nucleus) with treatment non-response and non-remission in MDD. Patients with MDD were recruited in the context of five clinical studies, including a total of 3,637 in iduals. PGSs were estimated using a Bayesian framework and continuous shrinkage priors (PRS-CS-auto) after standard genotype quality control and imputation. Logistic regressions were performed between PGSs and non-response or non-remission in each s le, adjusting for age, sex, baseline symptom severity, recruitment sites, and population stratification. Results were meta-analysed across s les, using a random-effect model. Caudate volume PGS was nominally associated with non-remission (OR=1.09, 95% CI=1.01–1.19, p=0.036). Leave-one-out sensitivity analyses suggested a possible association with the amygdala and thalamus PGSs. However, no association was significant after multiple testing correction. These results, although preliminary, suggest a possible link between caudate volume PGS and lack of symptom remission. Methodological improvements in PGSs estimation and statistical power may enhance their predictive performance and provide a contribution to precision psychiatry.
Publisher: Springer Science and Business Media LLC
Date: 15-08-2019
No related grants have been discovered for Alessio Squassina.