Expression quantitative trait loci (eQTL) mapping has successfully resolved some genome-wide asso... more Expression quantitative trait loci (eQTL) mapping has successfully resolved some genome-wide association study (GWAS) loci for complex traits1–6. However, there is a need for implementing additional “omic” approaches to untangle additional loci and provide a biological context for GWAS signals. We generated a detailed landscape of the genomic architecture of protein levels in multiple neurologically relevant tissues (brain, cerebrospinal fluid (CSF) and plasma), by profiling thousands of proteins in a large and well-characterized cohort. We identified 274, 127 and 32 protein quantitative loci (pQTL) for CSF, plasma and brain respectively. We demonstrated that cis-pQTL are more likely to be shared across tissues but trans-pQTL are tissue-specific. Between 78% to 87% of pQTL are not eQTL, indicating that protein levels have a different genetic architecture than gene expression. By combining our pQTL with Mendelian Randomization approaches we identified potential novel biomarkers and d...
Cerebrospinal fluid (CSF) levels of amyloid beta (Aβ), tau and p‐tau are the standard biomarkers ... more Cerebrospinal fluid (CSF) levels of amyloid beta (Aβ), tau and p‐tau are the standard biomarkers for diagnosis and progression of Alzheimer disease (AD). CSF levels of Alpha‐synuclein (α‐Syn) have not been very informative in Parkinson’s disease (PD). The burden of Aβ plaques and Tau tangles inversely correlates with cognitive status in PD cases with dementia. However. Lewy body aggregated correlates with dementia progression in PD. A systematic study of CSF biomarkers in PD is yet to be complete, thus, we aimed to investigate the relationship between dementia biomarkers and PD using polygenic risk scores and Mendelian Randomization.
Neurodegenerative diseases are characterized by progressive neuronal death, leading to loss of co... more Neurodegenerative diseases are characterized by progressive neuronal death, leading to loss of cognitive function. This process is thought to commence decades before symptom onset. Consequently, there is a dire need to characterize the pre‐clinical phase of neurodegenerative diseases to provide early intervention. We employed a Mendelian randomization approach to identify genetic overlap across neurological disorders and describe common disease mechanisms.
The identification of multiple genetic risk factors for Alzheimer Disease (AD) provides evidence ... more The identification of multiple genetic risk factors for Alzheimer Disease (AD) provides evidence to support that many pathways contribute to AD onset and progression. However, the metabolomic and lipidomic profiles in carriers of distinct genetic risk factors are not fully understood. The metabolome can provide a direct image of dysregulated pathways in the brain, including information on treatment targets. In this study, we interrogate the metabolomic and lipidomic signatures in the AD brain, including carriers of pathogenic variants in APP, PSEN1, and PSEN2 (autosomal dominant AD; ADAD), APOE ε4 and TREM2 risk variant carriers, and non-carrier sporadic AD (sAD). We generated metabolomic and lipidomic data from parietal cortical tissue from 366 participants with AD pathology and 26 cognitively unimpaired controls using the Metabolon global metabolomics platform. We identified 133 metabolites associated with disease status (FDR q-value<0.05). In sAD brains these include tryptopha...
Alpha-synuclein is the main protein component of Lewy bodies, the pathological hallmark of Parkin... more Alpha-synuclein is the main protein component of Lewy bodies, the pathological hallmark of Parkinson’s disease. However, genetic modifiers of cerebrospinal fluid (CSF) alpha-synuclein levels remain unknown. The use of CSF levels of amyloid beta1–42, total tau, and phosphorylated tau181 as quantitative traits in genetic studies have provided novel insights into Alzheimer’s disease pathophysiology. A systematic study of the genomic architecture of CSF biomarkers in Parkinson’s disease has not yet been conducted. Here, genome-wide association studies of CSF biomarker levels in a cohort of individuals with Parkinson’s disease and controls (N = 1960) were performed. PD cases exhibited significantly lower CSF biomarker levels compared to controls. A SNP, proxy for APOE ε4, was associated with CSF amyloid beta1–42 levels (effect = − 0.5, p = 9.2 × 10−19). No genome-wide loci associated with CSF alpha-synuclein, total tau, or phosphorylated tau181 levels were identified in PD cohorts. Polyg...
Alpha-Synuclein (a-Syn) is the main protein component of Lewy bodies (LB), the pathological hallm... more Alpha-Synuclein (a-Syn) is the main protein component of Lewy bodies (LB), the pathological hallmark of Parkinson's disease (PD). Cerebrospinal fluid (CSF) levels of a-Syn are not currently used as a clinical biomarker but may be a proxy for pathological a-Syn accumulation in the brain. Therefore, identifying genetic modifiers of CSF a-Syn levels could provide insights into the underlying molecular mechanisms leading to PD. However, genetic modifiers of CSF a-Syn levels remain unknown. CSF levels of amyloid beta1-42 (Ab42), total tau (t-tau), and phosphorylated tau181 (p-tau181) are standard biomarkers for the diagnosis of Alzheimer disease (AD); its use as quantitative traits in genetic studies have provided novel insights into AD pathophysiology. A systematic study of the genomic architecture of CSF biomarkers in PD has not been conducted. Here, genome-wide association studies (GWAS) were performed using CSF biomarker levels as quantitative traits in four PD cases and control ...
Expression quantitative trait loci (eQTL) mapping has successfully resolved some genome-wide asso... more Expression quantitative trait loci (eQTL) mapping has successfully resolved some genome-wide association study (GWAS) loci for complex traits1–6. However, there is a need for implementing additional “omic” approaches to untangle additional loci and provide a biological context for GWAS signals. We generated a detailed landscape of the genomic architecture of protein levels in multiple neurologically relevant tissues (brain, cerebrospinal fluid (CSF) and plasma), by profiling thousands of proteins in a large and well-characterized cohort. We identified 274, 127 and 32 protein quantitative loci (pQTL) for CSF, plasma and brain respectively. We demonstrated that cis-pQTL are more likely to be shared across tissues but trans-pQTL are tissue-specific. Between 78% to 87% of pQTL are not eQTL, indicating that protein levels have a different genetic architecture than gene expression. By combining our pQTL with Mendelian Randomization approaches we identified potential novel biomarkers and d...
Cerebrospinal fluid (CSF) levels of amyloid beta (Aβ), tau and p‐tau are the standard biomarkers ... more Cerebrospinal fluid (CSF) levels of amyloid beta (Aβ), tau and p‐tau are the standard biomarkers for diagnosis and progression of Alzheimer disease (AD). CSF levels of Alpha‐synuclein (α‐Syn) have not been very informative in Parkinson’s disease (PD). The burden of Aβ plaques and Tau tangles inversely correlates with cognitive status in PD cases with dementia. However. Lewy body aggregated correlates with dementia progression in PD. A systematic study of CSF biomarkers in PD is yet to be complete, thus, we aimed to investigate the relationship between dementia biomarkers and PD using polygenic risk scores and Mendelian Randomization.
Neurodegenerative diseases are characterized by progressive neuronal death, leading to loss of co... more Neurodegenerative diseases are characterized by progressive neuronal death, leading to loss of cognitive function. This process is thought to commence decades before symptom onset. Consequently, there is a dire need to characterize the pre‐clinical phase of neurodegenerative diseases to provide early intervention. We employed a Mendelian randomization approach to identify genetic overlap across neurological disorders and describe common disease mechanisms.
The identification of multiple genetic risk factors for Alzheimer Disease (AD) provides evidence ... more The identification of multiple genetic risk factors for Alzheimer Disease (AD) provides evidence to support that many pathways contribute to AD onset and progression. However, the metabolomic and lipidomic profiles in carriers of distinct genetic risk factors are not fully understood. The metabolome can provide a direct image of dysregulated pathways in the brain, including information on treatment targets. In this study, we interrogate the metabolomic and lipidomic signatures in the AD brain, including carriers of pathogenic variants in APP, PSEN1, and PSEN2 (autosomal dominant AD; ADAD), APOE ε4 and TREM2 risk variant carriers, and non-carrier sporadic AD (sAD). We generated metabolomic and lipidomic data from parietal cortical tissue from 366 participants with AD pathology and 26 cognitively unimpaired controls using the Metabolon global metabolomics platform. We identified 133 metabolites associated with disease status (FDR q-value<0.05). In sAD brains these include tryptopha...
Alpha-synuclein is the main protein component of Lewy bodies, the pathological hallmark of Parkin... more Alpha-synuclein is the main protein component of Lewy bodies, the pathological hallmark of Parkinson’s disease. However, genetic modifiers of cerebrospinal fluid (CSF) alpha-synuclein levels remain unknown. The use of CSF levels of amyloid beta1–42, total tau, and phosphorylated tau181 as quantitative traits in genetic studies have provided novel insights into Alzheimer’s disease pathophysiology. A systematic study of the genomic architecture of CSF biomarkers in Parkinson’s disease has not yet been conducted. Here, genome-wide association studies of CSF biomarker levels in a cohort of individuals with Parkinson’s disease and controls (N = 1960) were performed. PD cases exhibited significantly lower CSF biomarker levels compared to controls. A SNP, proxy for APOE ε4, was associated with CSF amyloid beta1–42 levels (effect = − 0.5, p = 9.2 × 10−19). No genome-wide loci associated with CSF alpha-synuclein, total tau, or phosphorylated tau181 levels were identified in PD cohorts. Polyg...
Alpha-Synuclein (a-Syn) is the main protein component of Lewy bodies (LB), the pathological hallm... more Alpha-Synuclein (a-Syn) is the main protein component of Lewy bodies (LB), the pathological hallmark of Parkinson's disease (PD). Cerebrospinal fluid (CSF) levels of a-Syn are not currently used as a clinical biomarker but may be a proxy for pathological a-Syn accumulation in the brain. Therefore, identifying genetic modifiers of CSF a-Syn levels could provide insights into the underlying molecular mechanisms leading to PD. However, genetic modifiers of CSF a-Syn levels remain unknown. CSF levels of amyloid beta1-42 (Ab42), total tau (t-tau), and phosphorylated tau181 (p-tau181) are standard biomarkers for the diagnosis of Alzheimer disease (AD); its use as quantitative traits in genetic studies have provided novel insights into AD pathophysiology. A systematic study of the genomic architecture of CSF biomarkers in PD has not been conducted. Here, genome-wide association studies (GWAS) were performed using CSF biomarker levels as quantitative traits in four PD cases and control ...
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Papers by jorge bahena