In advanced age, some individuals maintain a stable cognitive trajectory while others experience a rapid decline. Such variation in cognitive trajectory is only partially explained by traditional ...neurodegenerative pathologies. Hence, to identify new processes underlying variation in cognitive trajectory, we perform an unbiased proteome-wide association study of cognitive trajectory in a discovery (n = 104) and replication cohort (n = 39) of initially cognitively unimpaired, longitudinally assessed older-adult brain donors. We find 579 proteins associated with cognitive trajectory after meta-analysis. Notably, we present evidence for increased neuronal mitochondrial activities in cognitive stability regardless of the burden of traditional neuropathologies. Furthermore, we provide additional evidence for increased synaptic abundance and decreased inflammation and apoptosis in cognitive stability. Importantly, we nominate proteins associated with cognitive trajectory, particularly the 38 proteins that act independently of neuropathologies and are also hub proteins of protein co-expression networks, as promising targets for future mechanistic studies of cognitive trajectory.
Depression is a common condition, but current treatments are only effective in a subset of individuals. To identify new treatment targets, we integrated depression genome-wide association study ...(GWAS) results (N = 500,199) with human brain proteomes (N = 376) to perform a proteome-wide association study of depression followed by Mendelian randomization. We identified 19 genes that were consistent with being causal in depression, acting via their respective cis-regulated brain protein abundance. We replicated nine of these genes using an independent depression GWAS (N = 307,353) and another human brain proteomic dataset (N = 152). Eleven of the 19 genes also had cis-regulated mRNA levels that were associated with depression, based on integration of the depression GWAS with human brain transcriptomes (N = 888). Meta-analysis of the discovery and replication proteome-wide association study analyses identified 25 brain proteins consistent with being causal in depression, 20 of which were not previously implicated in depression by GWAS. Together, these findings provide promising brain protein targets for further mechanistic and therapeutic studies.
Several common psychiatric and neurodegenerative diseases share epidemiologic risk; however, whether they share pathophysiology is unclear and is the focus of our investigation. Using 25 GWAS results ...and LD score regression, we find eight significant genetic correlations between psychiatric and neurodegenerative diseases. We integrate the GWAS results with human brain transcriptomes (n = 888) and proteomes (n = 722) to identify cis- and trans- transcripts and proteins that are consistent with a pleiotropic or causal role in each disease, referred to as causal proteins for brevity. Within each disease group, we find many distinct and shared causal proteins. Remarkably, 30% (13 of 42) of the neurodegenerative disease causal proteins are shared with psychiatric disorders. Furthermore, we find 2.6-fold more protein-protein interactions among the psychiatric and neurodegenerative causal proteins than expected by chance. Together, our findings suggest these psychiatric and neurodegenerative diseases have shared genetic and molecular pathophysiology, which has important ramifications for early treatment and therapeutic development.
The biological processes that are disrupted in the Alzheimer's disease (AD) brain remain incompletely understood. In this study, we analyzed the proteomes of more than 1,000 brain tissues to reveal ...new AD-related protein co-expression modules that were highly preserved across cohorts and brain regions. Nearly half of the protein co-expression modules, including modules significantly altered in AD, were not observed in RNA networks from the same cohorts and brain regions, highlighting the proteopathic nature of AD. Two such AD-associated modules unique to the proteomic network included a module related to MAPK signaling and metabolism and a module related to the matrisome. The matrisome module was influenced by the APOE ε4 allele but was not related to the rate of cognitive decline after adjustment for neuropathology. By contrast, the MAPK/metabolism module was strongly associated with the rate of cognitive decline. Disease-associated modules unique to the proteome are sources of promising therapeutic targets and biomarkers for AD.
Genome-wide association studies (GWAS) have identified many risk loci for Alzheimer's disease (AD)
, but how these loci confer AD risk is unclear. Here, we aimed to identify loci that confer AD risk ...through their effects on brain protein abundance to provide new insights into AD pathogenesis. To that end, we integrated AD GWAS results with human brain proteomes to perform a proteome-wide association study (PWAS) of AD, followed by Mendelian randomization and colocalization analysis. We identified 11 genes that are consistent with being causal in AD, acting via their cis-regulated brain protein abundance. Nine replicated in a confirmation PWAS and eight represent new AD risk genes not identified before by AD GWAS. Furthermore, we demonstrated that our results were independent of APOE e4. Together, our findings provide new insights into AD pathogenesis and promising targets for further mechanistic and therapeutic studies.
Alzheimer's disease (AD) is influenced by both genetic and environmental factors; thus, brain epigenomic alterations may provide insights into AD pathogenesis. Multiple array-based Epigenome-Wide ...Association Studies (EWASs) have identified robust brain methylation changes in AD; however, array-based assays only test about 2% of all CpG sites in the genome. Here, we develop EWASplus, a computational method that uses a supervised machine learning strategy to extend EWAS coverage to the entire genome. Application to six AD-related traits predicts hundreds of new significant brain CpGs associated with AD, some of which are further validated experimentally. EWASplus also performs well on data collected from independent cohorts and different brain regions. Genes found near top EWASplus loci are enriched for kinases and for genes with evidence for physical interactions with known AD genes. In this work, we show that EWASplus implicates additional epigenetic loci for AD that are not found using array-based AD EWASs.
We generated an online brain pQTL resource for 7,376 proteins through the analysis of genetic and proteomic data derived from post-mortem samples of the dorsolateral prefrontal cortex of 330 older ...adults. The identified pQTLs tend to be non-synonymous variation, are over-represented among variants associated with brain diseases, and replicate well (77%) in an independent brain dataset. Comparison to a large study of brain eQTLs revealed that about 75% of pQTLs are also eQTLs. In contrast, about 40% of eQTLs were identified as pQTLs. These results are consistent with lower pQTL mapping power and greater evolutionary constraint on protein abundance. The latter is additionally supported by observations of pQTLs with large effects’ tending to be rare, deleterious, and associated with proteins that have evidence for fewer protein-protein interactions. Mediation analyses using matched transcriptomic and proteomic data provided additional evidence that pQTL effects are often, but not always, mediated by mRNA. Specifically, we identified roughly 1.6 times more mRNA-mediated pQTLs than mRNA-independent pQTLs (550 versus 341). Our pQTL resource provides insight into the functional consequences of genetic variation in the human brain and a basis for novel investigations of genetics and disease.
Abstract Resilience refers to abilities to cope adaptively with adversity or trauma. A common psychological sequella of childhood abuse or other traumatic experiences is substance use problems. There ...are, however, very limited data on relationships among resilience traits, childhood abuse, and alcohol or drug use problems. Hence, we aimed to examine associations between resilience characteristics and lifetime alcohol and illicit drug use in 2024 inner-city adults with high rates of childhood abuse and other trauma exposure. In this cross-sectional study, resilience was assessed with the Connor-Davidson Resilience Scale, childhood abuse with the Childhood Trauma Questionnaire, lifetime alcohol and illicit drug use with the Alcohol Use Disorder Identification Test and Drug Abuse Screening Test. Associations between resilience and substance use were examined with linear regression models, adjusting for trauma load, age, and sex. We found that resilience characteristics mitigated tendency for lifetime alcohol use problems both as a main effect ( β = −0.11; p = 0.0014) and an interaction with severity of childhood abuse ( β = −0.06; p = 0.0115) after trauma severity, age, and sex were controlled for. Similarly, resilience reduced lifetime illicit drug use both as a main effect ( β = −0.03; p = 0.0008) and as an interaction with severity of childhood abuse ( β = -0.01; p = 0.0256) after trauma load, age, and sex were adjusted for. Our findings add to a nascent body of literature suggesting that resilience characteristics mitigate risks not only for PTSD, major depression, and suicidality, but also for substance use problems in adults exposed to childhood abuse or other traumatic experiences.
Background: Functional recovery among treated bipolar disorder (BPD) patients is far less likely than syndromal and even symptomatic recovery. We hypothesized that increasingly well‐documented ...aspects of cognitive impairment may contribute to poor functional outcomes in BPD patients, and reviewed the available research on the topic.
Methods: Computerized literature searching identified 12 studies with 13 comparisons that simultaneously evaluated cognitive and functional status in euthymic (n = 8) or non‐euthymic (n = 5 comparisons) adult BPD patients versus otherwise similar healthy controls.
Results: In 6/8 studies of euthymic BPD patients and 5/5 studies of non‐euthymic BPD patients, neurocognitive impairment was significantly associated with impaired psychosocial functioning, even after adjusting for residual mood symptoms and relevant demographic and clinical variables. Cognitive status was consistently assessed with standardized, performance‐based neuropsychological tests, but functional status usually was based on subjective self‐appraisals. Approximately 55% of BPD patients were unemployed.
Conclusions: Available studies are limited by subjective assessments of functional status rather than objective, performance‐based measures. Nevertheless, they support the hypothesis that enduring aspects of cognitive impairment found even in euthymic BPD patients are associated with inferior functioning. These findings encourage further studies with better assessment methods and greater rehabilitative efforts in BPD patients.
The transcriptome-wide association studies (TWASs) that test for association between the study trait and the imputed gene expression levels from cis-acting expression quantitative trait loci ...(cis-eQTL) genotypes have successfully enhanced the discovery of genetic risk loci for complex traits. By using the gene expression imputation models fitted from reference datasets that have both genetic and transcriptomic data, TWASs facilitate gene-based tests with GWAS data while accounting for the reference transcriptomic data. The existing TWAS tools like PrediXcan and FUSION use parametric imputation models that have limitations for modeling the complex genetic architecture of transcriptomic data. Therefore, to improve on this, we employ a nonparametric Bayesian method that was originally proposed for genetic prediction of complex traits, which assumes a data-driven nonparametric prior for cis-eQTL effect sizes. The nonparametric Bayesian method is flexible and general because it includes both of the parametric imputation models used by PrediXcan and FUSION as special cases. Our simulation studies showed that the nonparametric Bayesian model improved both imputation R2 for transcriptomic data and the TWAS power over PrediXcan when ≥1% cis-SNPs co-regulate gene expression and gene expression heritability ≤0.2. In real applications, the nonparametric Bayesian method fitted transcriptomic imputation models for 57.8% more genes over PrediXcan, thus improving the power of follow-up TWASs. We implement both parametric PrediXcan and nonparametric Bayesian methods in a convenient software tool “TIGAR” (Transcriptome-Integrated Genetic Association Resource), which imputes transcriptomic data and performs subsequent TWASs using individual-level or summary-level GWAS data.
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