Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis

Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric = 1.28E–09 and 4.10E–18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.publishedVersio

Comparative Linkage Meta-Analysis Reveals Regionally-Distinct, Disparate Genetic Architectures: Application to Bipolar Disorder and Schizophrenia

New high-throughput, population-based methods and next-generation sequencing capabilities hold great promise in the quest for common and rare variant discovery and in the search for ”missing heritability.” However, the optimal analytic strategies for approaching such data are still actively debated, representing the latest rate-limiting step in genetic progress. Since it is likely a majority of common variants of modest effect have been identified through the application of tagSNP-based microarray platforms (i.e., GWAS), alternative approaches robust to detection of low-frequency (1–5% MAF) and rare (<1%) variants are of great importance. Of direct relevance, we have available an accumulated wealth of linkage data collected through traditional genetic methods over several decades, the full value of which has not been exhausted. To that end, we compare results from two different linkage meta-analysis methods—GSMA and MSP—applied to the same set of 13 bipolar disorder and 16 schizophrenia GWLS datasets. Interestingly, we find that the two methods implicate distinct, largely non-overlapping, genomic regions. Furthermore, based on the statistical methods themselves and our contextualization of these results within the larger genetic literatures, our findings suggest, for each disorder, distinct genetic architectures may reside within disparate genomic regions. Thus, comparative linkage meta-analysis (CLMA) may be used to optimize low-frequency and rare variant discovery in the modern genomic era

Modifying Dementia Risk and Trajectories of Cognitive Decline in Aging: The Cache County Memory Study

The Cache County Study of Memory, Health, and Aging, more commonly referred to as the “Cache County Memory Study (CCMS)” is a longitudinal investigation of aging and Alzheimer’s disease (AD) based in an exceptionally long-lived population residing in northern Utah. The study begun in 1994 has followed an initial cohort of 5,092 older individuals (many over age 84) and has examined the development of cognitive impairment and dementia in relation to genetic and environmental antecedents. This article summarizes the major contributions of the CCMS towards the understanding of mild cognitive disorders and AD across the lifespan, underscoring the role of common health exposures in modifying dementia risk and trajectories of cognitive change. The study now in its fourth wave of ascertainment illustrates the role of population-based approaches in informing testable models of cognitive aging and Alzheimer’s disease

Better Cognitive Performance in Elderly Taking Antioxidant Vitamins E and C Supplements in Combination with Nonsteroidal Anti-Inflammatory drugs: The Cache County Study

Studies have shown less cognitive decline and lower risk of Alzheimer\u27s disease in elderly individuals consuming either antioxidant vitamins or nonsteroidal anti-inflammatory drugs (NSAIDs). The potential of added benefit from their combined use has not been studied. We therefore analyzed data from 3,376 elderly participants of the Cache County Study who were given the Modified Mini-Mental State examination up to three times during a period of 8 years. Those who used a combination of vitamins E and C supplements and NSAIDs at baseline declined by an average 0.96 fewer points every 3 years than nonusers (P \u3c .05). This apparent effect was attributable entirely to participants with the APOE ε4 allele, whose users declined by 2.25 fewer points than nonusers every 3 years (P \u3c .05). These results suggest that among elderly individuals with an APOE ε4 allele, there is an association between using antioxidant supplements in combination with NSAIDs and less cognitive decline over time

Anti-Hypertensive Medication Use and Incident Alzheimer\u27s Disease. The Cache County Study

Background: Recent reports suggest that antihypertensive (AH) medications may reduce the risk of dementing illnesses. Objectives: To examine the relationship of AH medication use with incidence of Alzheimer disease (AD) among the elderly population (aged 65 years and older) of Cache County, Utah, and to examine whether the relationship varies with different classes of AH medications. Methods: After an initial (wave 1) multistage assessment (1995 through 1997) to identify prevalent cases of dementia, we used similar methods 3 years later (wave 2) to identify 104 incident cases of AD among the 3308 survivors. At the baseline assessment, we obtained a detailed drug inventory from the study participants. We carried out discrete time survival analyses to examine the association between the use of AH medications (including angiotensin converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics) at baseline with subsequent risk of AD. Results: Use of any AH medication at baseline was associated with lower incidence of AD (adjusted hazard ratio, 0.64; 95% confidence interval, 0.41-0.98). Examination of medication subclasses showed that use of diuretics (adjusted hazard ratio, 0.57; 95% confidence interval, 0.33-0.94), and specifically potassium-sparing diuretics (adjusted hazard ratio, 0.26; 95% confidence interval, 0.08-0.64), was associated with the greatest reduction in risk of AD. Corresponding analysis with a fully examined subsample controlling for blood pressure measurements did not substantially change our findings. Conclusions: These data suggest that AH medications, and specifically potassium-sparing diuretics, are associated with reduced incidence of AD. Because the latter association is a new finding, it requires confirmation in further study

Do Statins Reduce Risk of Incident Dementia and Alzheimer\u27s Disease? The Cache County Study

Background: Prior reports suggest reduced occurrence of dementia and Alzheimer disease (AD) in statin users, but, to our knowledge, no prospective studies relate statin use and dementia incidence. Objective: To examine the association of statin use with both prevalence and incidence of dementia and AD. Design: Cross-sectional studies of prevalence and incidence and a prospective study of incidence of dementia and AD among 5092 elderly residents (aged 65 years or older) of a single county. Participants were assessed at home in 1995-1997 and again in 1998-2000. A detailed visual inventory of medicines, including statins and other lipid-lowering agents, was collected at both assessments. Main Outcome Measures: Diagnosis of dementia and of AD. Results: From 4895 participants with data sufficient to determine cognitive status, we identified 355 cases of prevalent dementia (200 with AD) at initial assessment. Statin use was inversely associated with prevalence of dementia (adjusted odds ratio, 0.44; 95% confidence interval, 0.17-0.94). Three years later, we identified 185 cases of incident dementia (104 with AD) among 3308 survivors at risk. Statin use at baseline did not predict incidence of dementia or AD (adjusted hazard ratio for dementia, 1.19; 95% confidence interval, 0.53-2.34; adjusted hazard ratio for AD, 1.19; 95% confidence interval, 0.35-2.96), nor did statin use at follow-up (adjusted odds ratio for dementia, 1.04; 95% confidence interval, 0.56-1.81; adjusted odds ratio for AD, 0.85; 95% confidence interval, 0.32-1.88). Conclusions: Although statin use might be less frequent in those with prevalent dementia, we found no association between statin use and subsequent onset of dementia or AD. Further research is warranted before costly dementia prevention trials with statins are undertaken

Vascular Risk Factors for Incident Alzheimer Disease and Vascular Dementia: The Cache County Study

Vascular risk factors for Alzheimer disease (AD) and vascular dementia (VaD) have been evaluated; however, few studies have compared risks by dementia subtypes and sex. We evaluated relationships between cardiovascular risk factors (hypertension, high cholesterol, diabetes mellitus, and obesity), events (stroke, coronary artery bypass graft surgery, and myocardial infarction), and subsequent risk of AD and VaD by sex in a community-based cohort of 3264 Cache County residents aged 65 or older. Cardiovascular history was ascertained by self-report or proxy-report in detailed interviews. AD and VaD were diagnosed using standard criteria. Estimates from discrete-time survival models showed no association between self-reported history of hypertension and high cholesterol and AD after adjustments. Hypertension increased the risk of VaD [adjusted hazard ratio (aHR) 2.42, 95% confidence interval (CI) 0.95-7.44]. Obesity increased the risk of AD in females (aHR 2.23, 95% CI 1.09-4.30) but not males. Diabetes increased the risk of VaD in females after adjustments (aHR 3.33, 95% CI 1.03-9.78) but not males. The risk of VaD after stroke was increased in females (aHR 16.90, 95% CI 5.58-49.03) and males (aHR 10.95, 95% CI 2.48-44.78). The results indicate that vascular factors increase risks for AD and VaD differentially by sex. Future studies should focus on specific causal pathways for each of these factors with regard to sex to determine if sex differences in the prevalence of vascular factors have an influence on sex differences in dementia risk

A Population Study of Alzheimer\u27s Disease: Findings From the Cache County Study on Memory, Health, and Aging

There are several population-based studies of aging, memory, and dementia being conducted worldwide. Of these, the Cache County Study on Memory, Health and Aging is noteworthy for its large number of oldest-old members. This study, which has been following an initial cohort of 5,092 seniors since 1995, has reported among its major findings the role of the Apolipoprotein E gene on modifying the risk for Alzheimer\u27s disease (AD) in males and females and identifying pharmacologic compounds that may act to reduce AD risk. This article summarizes the major findings of the Cache County study to date, describes ongoing investigations, and reports preliminary analyses on the outcome of the oldest-old in this population, the subgroup of participants who were over age 84 at the study\u27s inception