An atlas of cortical circular RNA expression in Alzheimer disease brains demonstrates clinical and pathological associations.

Parietal cortex RNA-sequencing (RNA-seq) data were generated from individuals with and without Alzheimer disease (AD; ncontrol = 13; nAD = 83) from the Knight Alzheimer Disease Research Center (Knight ADRC). Using this and an independent (Mount Sinai Brain Bank (MSBB)) AD RNA-seq dataset, cortical circular RNA (circRNA) expression was quantified in the context of AD. Significant associations were identified between circRNA expression and AD diagnosis, clinical dementia severity and neuropathological severity. It was demonstrated that most circRNA-AD associations are independent of changes in cognate linear messenger RNA expression or estimated brain cell-type proportions. Evidence was provided for circRNA expression changes occurring early in presymptomatic AD and in autosomal dominant AD. It was also observed that AD-associated circRNAs co-expressed with known AD genes. Finally, potential microRNA-binding sites were identified in AD-associated circRNAs for miRNAs predicted to target AD genes. Together, these results highlight the importance of analyzing non-linear RNAs and support future studies exploring the potential roles of circRNAs in AD pathogenesis

Functional genomic analyses uncover APOE-mediated regulation of brain and cerebrospinal fluid beta-amyloid levels in Parkinson disease

Alpha-synuclein is the main protein component of Lewy bodies, the pathological hallmark of Parkinson\u27s disease. However, genetic modifiers of cerebrospinal fluid (CSF) alpha-synuclein levels remain unknown. The use of CSF levels of amyloid bet

Polygenic and Transcriptomic Studies in Neurodegeneration: Towards More Precise Medicine.

Precision medicine defines both health and disease in terms of high dimensional data. In my thesis work, I apply current knowledge and tools of precision medicine to better understand the etiopathogenesis of neurodegenerative diseases (NDs). Genome-wide association studies (GWAS) have demonstrated that genetic susceptibility for NDs and other diseases is mediated by many common genetic variants of modest effect size which contribute to disease risk in a polygenic or even omnigenic manner. These complex genetics render prioritizing genes to better understand the disease and potentially identify therapeutic targets, challenging. In the first half of this thesis, I address this challenge by leveraging the comorbidity between Parkinson disease (PD) and cutaneous melanoma (melanoma). I apply modern linkage disequilibrium-informed methods to the currently largest available GWAS summary statistics for PD and melanoma to identify shared genetic architecture between these diseases and prioritize genes whose inferred expression is commonly impacted by disease-associated genetic variants for downstream functional analyses. Comparing gene expression in disease-relevant tissues can directly identify disease-associated genes. The majority of such transcriptomic studies in NDs have focused on the linear, protein-coding transcriptome. However, non-messenger RNAs, such as circular RNAs (circRNAs), have important regulatory functions under both physiologic and pathologic conditions. In the second half of this thesis, I analyze circular RNA differential expression in human brain tissues donated by individuals with and without neuropathologically-diagnosed Alzheimer disease (AD). I identify significant associations with circRNAs and AD and provide evidence for expression changes occurring before the onset of clinical dementia symptoms. I also demonstrate that AD-associated circRNAs co-express with known AD genes and pathways and yield strong predictive ability for AD case status, even in the absence of demographic or genetic risk factor data. Together, my results support future studies exploring circRNAs as biomarkers for AD and for the potential roles in AD pathogenesis. In conclusion, my dissertation work demonstrates the utility of applying the methods of precision medicine to better understand the etiopathogenesis of NDs. My analysis approaches can be applied to other diseases and complex traits as more genomic and transcriptomic data become available

Use of medical care biases associations between Parkinson disease and other medical conditions

OBJECTIVE: To examine how use of medical care biases the well-established associations between Parkinson disease (PD) and smoking, smoking-related cancers, and selected positively associated comorbidities. METHODS: We conducted a population-based, case-control study of 89,790 incident PD cases and 118,095 randomly selected controls, all Medicare beneficiaries aged 66 to 90 years. We ascertained PD and other medical conditions using ICD-9-CM codes from comprehensive claims data for the 5 years before PD diagnosis/reference. We used logistic regression to estimate age-, sex-, and race-adjusted odds ratios (ORs) between PD and each other medical condition of interest. We then examined the effect of also adjusting for selected geographic- or individual-level indicators of use of care. RESULTS: Models without adjustment for use of care and those that adjusted for geographic-level indicators produced similar ORs. However, adjustment for individual-level indicators consistently decreased ORs: Relative to ORs without adjustment for use of care, all ORs were between 8% and 58% lower, depending on the medical condition and the individual-level indicator of use of care added to the model. ORs decreased regardless of whether the established association is known to be positive or inverse. Most notably, smoking and smoking-related cancers were positively associated with PD without adjustment for use of care, but appropriately became inversely associated with PD with adjustment for use of care. CONCLUSION: Use of care should be considered when evaluating associations between PD and other medical conditions to ensure that positive associations are not attributable to bias and that inverse associations are not masked

Well Water and Parkinson\u27s Disease in Medicare Beneficiaries: A Nationwide Case-Control Study

BACKGROUND: Well water frequently is considered a risk factor for Parkinson\u27s disease (PD), but few studies were designed appropriately to test whether geographic factors affect PD risk. OBJECTIVE: To determine the risk of PD in relation to residential use of private well water. METHODS: In a nationwide, population-based case-control study, we identified all incident PD cases (N = 89,790) and all comparable controls (N = 21,549,400) age 66-90 who solely relied on Medicare coverage in the U.S. in 2009. We estimated the probability of use of private well water using zip code of residence at diagnosis/reference and U.S. Census data on household water source. We modeled this exposure linearly in logistic regression to calculate the odds ratio (OR) and 95% confidence interval (CI) of PD risk in relation to well water use. We adjusted for age, sex and race/ethnicity, and verified that smoking and use of medical care did not confound results. We repeated analyses with a 2-year exposure lag and separately within each U.S. state. RESULTS: Use of well water was inversely associated with PD risk (OR = 0.87, 95% CI 0.85-0.89). We confirmed this association in a Cox survival analysis in which we followed controls for 5 years, death or PD diagnosis. There was little evidence that well water use increased risk of PD in any individual state. CONCLUSIONS: Although it remains possible that exposures in well water in more narrow geographic regions increase PD risk, in general these results suggest that exposures more common in urban/suburban areas might also be relevant

Overlapping genetic architecture between Parkinson disease and melanoma

Epidemiologic studies have reported inconsistent results regarding an association between Parkinson disease (PD) and cutaneous melanoma (melanoma). Identifying shared genetic architecture between these diseases can support epidemiologic findings and identify common risk genes and biological pathways. Here, we apply polygenic, linkage disequilibrium-informed methods to the largest available case-control, genome-wide association study summary statistic data for melanoma and PD. We identify positive and significant genetic correlation (correlation: 0.17, 95% CI 0.10-0.24; P = 4.09 × 10-06) between melanoma and PD. We further demonstrate melanoma and PD-inferred gene expression to overlap across tissues (correlation: 0.14, 95% CI 0.06 to 0.22; P = 7.87 × 10-04) and highlight seven genes including PIEZO1, TRAPPC2L, and SOX6 as potential mediators of the genetic correlation between melanoma and PD. These findings demonstrate specific, shared genetic architecture between PD and melanoma that manifests at the level of gene expression