scholarly journals Novel polygenic risk score as a translational tool linking depression-related changes in the corticolimbic transcriptome with neural face processing and anhedonic symptoms

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Klara Mareckova ◽  
Colin Hawco ◽  
Fernanda C. Dos Santos ◽  
Arin Bakht ◽  
Navona Calarco ◽  
...  
Keyword(s):  
Gene Expression ◽  
Risk Score ◽  
Activity Patterns ◽  
Expression Patterns ◽  
Neural Response ◽  
Postmortem Brain ◽  
Polygenic Risk Score ◽  
Least Squares Regression ◽  
Social Stimuli ◽  
Polygenic Risk

AbstractConvergent data from imaging and postmortem brain transcriptome studies implicate corticolimbic circuit (CLC) dysregulation in the pathophysiology of depression. To more directly bridge these lines of work, we generated a novel transcriptome-based polygenic risk score (T-PRS), capturing subtle shifts toward depression-like gene expression patterns in key CLC regions, and mapped this T-PRS onto brain function and related depressive symptoms in a nonclinical sample of 478 young adults (225 men; age 19.79 +/− 1.24) from the Duke Neurogenetics Study. First, T-PRS was generated based on common functional SNPs shifting CLC gene expression toward a depression-like state. Next, we used multivariate partial least squares regression to map T-PRS onto whole-brain activity patterns during perceptual processing of social stimuli (i.e., human faces). For validation, we conducted a comparative analysis with a PRS summarizing depression risk variants identified by the Psychiatric Genomics Consortium (PGC-PRS). Sex was modeled as moderating factor. We showed that T-PRS was associated with widespread reductions in neural response to neutral faces in women and to emotional faces and shapes in men (multivariate p < 0.01). This female-specific reductions in neural response to neutral faces was also associated with PGC-PRS (multivariate p < 0.03). Reduced reactivity to neutral faces was further associated with increased self-reported anhedonia. We conclude that women with functional alleles mimicking the postmortem transcriptomic CLC signature of depression have blunted neural activity to social stimuli, which may be expressed as higher anhedonia.

scholarly journals Novel polygenic risk score as a translational tool linking depression-related changes in the corticolimbic transcriptome with neural face processing and anhedonic symptoms

2019 ◽  
Author(s):  
Klara Mareckova ◽  
Colin Hawco ◽  
Fernanda C. Dos Santos ◽  
Arin Bakht ◽  
Navona Calarco ◽  
...  
Keyword(s):  
Gene Expression ◽  
Risk Score ◽  
Clinical Sample ◽  
Expression Patterns ◽  
Neural Response ◽  
Postmortem Brain ◽  
Polygenic Risk Score ◽  
Least Squares Regression ◽  
Social Stimuli ◽  
Polygenic Risk

ABSTRACTConvergent data from imaging and postmortem brain transcriptome studies implicate corticolimbic circuit (CLC) dysregulation in the pathophysiology of depression. To more directly bridge these lines of work, we generated a novel transcriptome-based polygenic risk score (T-PRS), capturing subtle shifts towards depression-like gene expression patterns in key CLC regions, and mapped this T-PRS onto brain function and related depressive symptoms in a non-clinical sample of 478 young adults (225 men; age 19.79+/−1.24) from the Duke Neurogenetics Study. First, T-PRS was generated based on common functional SNPs shifting CLC gene expression towards a depression-like state. Next, we used multivariate partial least squares regression to map T-PRS onto whole-brain activity patterns during perceptual processing of social stimuli (i.e., human faces). For validation, we conducted a comparative analysis with a PRS summarizing depression risk variants identified by the Psychiatric Genomics Consortium (PGC-PRS). Sex was modeled as moderating factor. We showed that T-PRS was associated with widespread reductions in neural response to neutral faces in women and to emotional faces and shapes in men (multivariate p<0.01). This female-specific reductions in neural response to neutral faces was also associated with PGC-PRS (multivariate p<0.03). Reduced reactivity to neutral faces was further associated with increased self-reported anhedonia. We conclude that women with functional alleles mimicking the postmortem transcriptomic CLC signature of depression have blunted neural activity to social stimuli, which may be expressed as higher anhedonia.

scholarly journals Novel polygenic risk score links depression-related cortical transcriptomic changes to brain morphology and symptom severity

2021 ◽  
Author(s):  
Amy E Miles ◽  
Fernanda C Dos Santos ◽  
Enda M Byrne ◽  
Miguel E Renteria ◽  
Andrew M McIntosh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Risk Score ◽  
Symptom Severity ◽  
Self Report ◽  
Brain Morphology ◽  
Polygenic Risk Score ◽  
Depression Diagnosis ◽  
Polygenic Risk ◽  
Depression Risk ◽  
Common Genetic Variants

ABSTRACTOur group developed a transcriptome-based polygenic risk score (T-PRS) that uses common genetic variants to capture ‘depression-like’ shifts in cortical gene expression. Here, we mapped T-PRS onto diagnosis and symptom severity in major depressive disorder (MDD) cases and controls from the Psychiatric Genomics Consortium (PGC). To evaluate potential mechanisms, we further mapped T-PRS onto discrete measures of brain morphology and broad depression risk in healthy young adults. Genetic, self-report, and/or neuroimaging data were available in 29,340 PGC participants (59% women; 12,923 MDD cases, 16,417 controls) and 482 participants in the Duke Neurogenetics Study (DNS: 53% women; aged 19.8±1.2 years). T-PRS was computed from SNP data using PrediXcan to impute cortical expression levels of MDD-related genes from a previous post-mortem transcriptome meta-analysis. Sex-specific regressions were used to test effects of T-PRS on depression diagnosis, symptom severity, and Freesurfer-derived subcortical volume, cortical thickness, surface area, and local gyrification index in the PGC and DNS samples, respectively. T-PRS did not predict depression diagnosis (OR=1.007, 95%CI=[0.997-1.018]); however, it correlated with symptom severity in men (rho=0.175, p=7.957×10−4) in one large PGC cohort (N=762, 48% men). In DNS, T-PRS was associated with smaller amygdala volume in women (β=-0.186, t=-3.478, p=.001) and less prefrontal gyrification (max≤-2.970, p≤.006) in both sexes. In men, prefrontal gyrification mediated an indirect effect of T-PRS on broad depression risk (b=.005, p=.029), indexed using self-reported family history of depression. Depression-like shifts in cortical gene expression predict symptom severity in men and may contribute to disease vulnerability through their effect on cortical gyrification.

1645-P: Polygenic Risk Score for Prediction of Complications in Men and Women with Type 2 Diabetes

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 1645-P
Author(s):  
JOHANNE TREMBLAY ◽  
REDHA ATTAOUA ◽  
MOUNSIF HALOUI ◽  
RAMZAN TAHIR ◽  
CAROLE LONG ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Risk Score ◽  
Polygenic Risk Score ◽  
Men And Women ◽  
Polygenic Risk ◽  
Prediction Of Complications

304-OR: Polygenic Risk Score Predicts Type 2 Diabetes Susceptibility in a Diverse Consumer Genetic Database

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 304-OR
Author(s):  
MICHAEL L. MULTHAUP ◽  
RYOSUKE KITA ◽  
NICHOLAS ERIKSSON ◽  
STELLA ASLIBEKYAN ◽  
JANIE SHELTON ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Risk Score ◽  
Polygenic Risk Score ◽  
Diabetes Susceptibility ◽  
Genetic Database ◽  
Polygenic Risk

P4-240: Using polygenic risk score to predict Alzheimer's disease

2015 ◽  
Vol 11 (7S_Part_19) ◽  
pp. P872-P872 ◽  
Author(s):  
Valentina Escott-Price ◽  
Rebecca Sims ◽  
Denise Harold ◽  
Maria Vronskaya ◽  
Peter Holmans ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Score ◽  
Polygenic Risk Score ◽  
Polygenic Risk

scholarly journals Relative contributions of family history and a polygenic risk score on COPD and related outcomes: COPDGene and ECLIPSE studies

2020 ◽  
Vol 7 (1) ◽  
pp. e000755
Author(s):  
Matthew Moll ◽  
Sharon M. Lutz ◽  
Auyon J. Ghosh ◽  
Phuwanat Sakornsakolpat ◽  
Craig P. Hersh ◽  
...  
Keyword(s):  
Family History ◽  
Risk Score ◽  
Characteristic Curve ◽  
Significant Proportion ◽  
Chronic Obstructive ◽  
Polygenic Risk Score ◽  
Positive Interaction ◽  
Polygenic Risk ◽  
Mediation Analyses ◽  
The Impact

IntroductionFamily history is a risk factor for chronic obstructive pulmonary disease (COPD). We previously developed a COPD risk score from genome-wide genetic markers (Polygenic Risk Score, PRS). Whether the PRS and family history provide complementary or redundant information for predicting COPD and related outcomes is unknown.MethodsWe assessed the predictive capacity of family history and PRS on COPD and COPD-related outcomes in non-Hispanic white (NHW) and African American (AA) subjects from COPDGene and ECLIPSE studies. We also performed interaction and mediation analyses.ResultsIn COPDGene, family history and PRS were significantly associated with COPD in a single model (PFamHx <0.0001; PPRS<0.0001). Similar trends were seen in ECLIPSE. The area under the receiver operator characteristic curve for a model containing family history and PRS was significantly higher than a model with PRS (p=0.00035) in NHWs and a model with family history (p<0.0001) alone in NHWs and AAs. Both family history and PRS were significantly associated with measures of quantitative emphysema and airway thickness. There was a weakly positive interaction between family history and the PRS under the additive, but not multiplicative scale in NHWs (relative excess risk due to interaction=0.48, p=0.04). Mediation analyses found that a significant proportion of the effect of family history on COPD was mediated through PRS in NHWs (16.5%, 95% CI 9.4% to 24.3%), but not AAs.ConclusionFamily history and the PRS provide complementary information for predicting COPD and related outcomes. Future studies can address the impact of obtaining both measures in clinical practice.

scholarly journals Polygenic risk score and risk of monoclonal B-cell lymphocytosis in caucasians and risk of chronic lymphocytic leukemia (CLL) in African Americans

Leukemia ◽  
2021 ◽  
Author(s):  
Geffen Kleinstern ◽  
J. Brice Weinberg ◽  
Sameer A. Parikh ◽  
Esteban Braggio ◽  
Sara J. Achenbach ◽  
...  
Keyword(s):  
Environmental Factors ◽  
B Cell ◽  
Risk Score ◽  
Genetic Factors ◽  
Strong Predictor ◽  
Lymphocytic Leukemia ◽  
European Ancestry ◽  
Polygenic Risk Score ◽  
Polygenic Risk ◽  
C Statistic

AbstractMonoclonal B-cell lymphocytosis (MBL) is a precursor to CLL. Other than age, sex, and CLL family-history, little is known about factors associated with MBL risk. A polygenic-risk-score (PRS) of 41 CLL-susceptibility variants has been found to be associated with CLL risk among individuals of European-ancestry(EA). Here, we evaluate these variants, the PRS, and environmental factors for MBL risk. We also evaluate these variants and the CLL-PRS among African-American (AA) and EA-CLL cases and controls. Our study included 560 EA MBLs, 869 CLLs (696 EA/173 AA), and 2866 controls (2631 EA/235 AA). We used logistic regression, adjusting for age and sex, to estimate odds ratios (OR) and 95% confidence intervals within each race. We found significant associations with MBL risk among 21 of 41 variants and with the CLL-PRS (OR = 1.86, P = 1.9 × 10−29, c-statistic = 0.72). Little evidence of any association between MBL risk and environmental factors was observed. We observed significant associations of the CLL-PRS with EA-CLL risk (OR = 2.53, P = 4.0 × 10−63, c-statistic = 0.77) and AA-CLL risk (OR = 1.76, P = 5.1 × 10−5, c-statistic = 0.62). Inherited genetic factors and not environmental are associated with MBL risk. In particular, the CLL-PRS is a strong predictor for both risk of MBL and EA-CLL, but less so for AA-CLL supporting the need for further work in this population.

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