ORCID Profile
0000-0001-5766-8923
Current Organisations
University of California, San Diego
,
Veterans Affairs San Diego Healthcare System
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Publisher: Springer Science and Business Media LLC
Date: 27-01-2020
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: Elsevier BV
Date: 02-2015
Publisher: Research Square Platform LLC
Date: 03-10-2023
Publisher: American Psychiatric Association Publishing
Date: 11-2009
Publisher: Elsevier BV
Date: 03-2016
Publisher: Elsevier BV
Date: 02-2019
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: 11-07-2022
Publisher: Springer Science and Business Media LLC
Date: 2010
DOI: 10.1038/NMETH0110-06
Publisher: Public Library of Science (PLoS)
Date: 09-01-2009
Publisher: Elsevier BV
Date: 2011
Publisher: Springer Science and Business Media LLC
Date: 05-05-2016
Publisher: Cold Spring Harbor Laboratory
Date: 02-09-2023
Publisher: Springer Science and Business Media LLC
Date: 08-10-2019
DOI: 10.1038/S41467-019-12576-W
Abstract: The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5–20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson’s disease gene involved in dopamine regulation, PARK2 , is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.
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: Cold Spring Harbor Laboratory
Date: 08-11-2022
DOI: 10.1101/2022.11.04.515213
Abstract: Genetic contributions to human cortical structure manifest pervasive pleiotropy. This pleiotropy may be harnessed to identify unique genetically-informed parcellations of the cortex that are neurobiologically distinct from anatomical, functional, cytoarchitectural, or other cortical parcellation schemes. We investigated genetic pleiotropy by applying genomic structural equation modeling (SEM) to model the genetic architecture of cortical surface area (SA) and cortical thickness (CT) of 34 brain regions recently reported in the ENIGMA cortical GWAS. Genomic SEM uses the empirical genetic covariance estimated from GWAS summary statistics with LD score regression (LDSC) to discover factors underlying genetic covariance. Genomic SEM can fit a multivariate GWAS from summary statistics, which can subsequently be used for LD score regression (LDSC). We found the best-fitting model of cortical SA was explained by 6 latent factors and CT was explained by 4 latent factors. The multivariate GWAS of these latent factors identified 74 genome-wide significant (GWS) loci (p ×10 −8 ), including many previously implicated in neuroimaging phenotypes, behavioral traits, and psychiatric conditions. LDSC of latent factor GWAS results found that SA-derived factors had a positive genetic correlation with bipolar disorder (BPD), and major depressive disorder (MDD), and a negative genetic correlation with attention deficit hyperactivity disorder (ADHD), MDD, and insomnia, while CT factors displayed a negative genetic correlation with alcohol dependence. Jointly modeling the genetic architecture of complex traits and investigating multivariate genetic links across phenotypes offers a new vantage point for mapping genetically informed cortical networks. Genomic SEM can examine genetic correlation across cortical regions. We inferred regional genetic networks of cortical thickness and surface area. Network-associated variants have been implicated in multiple traits. These networks are genetically correlated with several psychiatric disorders including MDD, bipolar, ADHD, and alcohol dependence.
Publisher: Wiley
Date: 06-12-2021
DOI: 10.1111/BDI.13162
Abstract: Bipolar disorder (BD) is characterized by episodes of depression and mania and disrupted circadian rhythms. Lithium is an effective therapy for BD, but only 30%–40% of patients are fully responsive. Preclinical models show that lithium alters circadian rhythms. However, it is unknown if the circadian rhythm effects of lithium are essential to its therapeutic properties. In secondary analyses of a multi‐center, prospective, trial of lithium for BD, we examined the relationship between circadian rhythms and therapeutic response to lithium. Using standardized instruments, we measured morningness, diurnal changes in mood, sleep, and energy (circadian rhythm disturbances) in a cross‐sectional study of 386 BD subjects with varying lithium exposure histories. Next, we tracked symptoms of depression and mania prospectively over 12 weeks in a subset of 88 BD patients initiating treatment with lithium. Total, circadian, and affective mood symptoms were scored separately and analyzed. Subjects with no prior lithium exposure had the most circadian disruption, while patients stable on lithium monotherapy had the least. Patients who were stable on lithium with another drug or unstable on lithium showed intermediate levels of disruption. Treatment with lithium for 12 weeks yielded significant reductions in total and affective depression symptoms. Lithium responders (Li‐Rs) showed improvement in circadian symptoms of depression, but non‐responders did not. There was no difference between Li‐Rs and nonresponders in affective, circadian, or total symptoms of mania. Exposure to lithium is associated with reduced circadian disruption. Lithium response at 12 weeks was selectively associated with the reduction of circadian depressive symptoms. We conclude that stabilization of circadian rhythms may be an important feature of lithium's therapeutic effects. Clinical Trials Registry: NCT0127253.
Publisher: Elsevier BV
Date: 10-2012
Publisher: Springer Science and Business Media LLC
Date: 11-08-2202
DOI: 10.1038/NG.2711
Location: United States of America
Location: No location found
Location: United States of America
No related grants have been discovered for Caroline Nievergelt.