Person: Anderson, Christopher
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Anderson
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Christopher
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Anderson, Christopher
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Publication Gene expression analysis uncovers novel hedgehog interacting protein (HHIP) effects in human bronchial epithelial cells(Elsevier BV, 2013) Zhou, Xiaobo; Qiu, Weiliang; Sathirapongsasuti, J. Fah; Cho, Michael; Mancini, John D.; Lao, Taotao; Thibault, Derek M.; Litonjua, Augusto A.; Bakke, Per S.; Gulsvik, Amund; Lomas, David A.; Beaty, Terri H.; Hersh, Craig; Anderson, Christopher; Geigenmuller, Ute; Raby, Benjamin; Rennard, Stephen I.; Perrella, Mark; Choi, Augustine M.K.; Quackenbush, John; Silverman, EdwinHedgehog Interacting Protein (HHIP) was implicated in chronic obstructive pulmonary disease (COPD) by genome-wide association studies (GWAS). However, it remains unclear how HHIP contributes to COPD pathogenesis. To identify genes regulated by HHIP, we performed gene expression microarray analysis in a human bronchial epithelial cell line (Beas-2B) stably infected with HHIP shRNAs. HHIP silencing led to differential expression of 296 genes; enrichment for variants nominally associated with COPD was found. Eighteen of the differentially expressed genes were validated by real-time PCR in Beas-2B cells. Seven of 11 validated genes tested in human COPD and control lung tissues demonstrated significant gene expression differences. Functional annotation indicated enrichment for extracellular matrix and cell growth genes. Network modeling demonstrated that the extracellular matrix and cell proliferation genes influenced by HHIP tended to be interconnected. Thus, we identified potential HHIP targets in human bronchial epithelial cells that may contribute to COPD pathogenesis.Publication Genetic variants in CETP increase risk of intracerebral hemorrhage(John Wiley and Sons Inc., 2016) Anderson, Christopher; Falcone, Guido J.; Phuah, Chia‐Ling; Radmanesh, Farid; Brouwers, H. Bart; Battey, Thomas W. K.; Biffi, Alessandro; Peloso, Gina M.; Liu, Dajiang J.; Ayres, Alison M.; Goldstein, Joshua N.; Viswanathan, Anand; Greenberg, Steven M.; Selim, Magdy; Meschia, James F.; Brown, Devin L.; Worrall, Bradford B.; Silliman, Scott L.; Tirschwell, David L.; Flaherty, Matthew L.; Kraft, Phillip; Jagiella, Jeremiasz M.; Schmidt, Helena; Hansen, Björn M.; Jimenez‐Conde, Jordi; Giralt‐Steinhauer, Eva; Elosua, Roberto; Cuadrado‐Godia, Elisa; Soriano, Carolina; van Nieuwenhuizen, Koen M.; Klijn, Catharina J. M.; Rannikmae, Kristiina; Samarasekera, Neshika; Salman, Rustam Al‐Shahi; Sudlow, Catherine L.; Deary, Ian J.; Morotti, Andrea; Pezzini, Alessandro; Pera, Joanna; Urbanik, Andrzej; Pichler, Alexander; Enzinger, Christian; Norrving, Bo; Montaner, Joan; Fernandez‐Cadenas, Israel; Delgado, Pilar; Roquer, Jaume; Lindgren, Arne; Slowik, Agnieszka; Schmidt, Reinhold; Kidwell, Chelsea S.; Kittner, Steven J.; Waddy, Salina P.; Langefeld, Carl D.; Abecasis, Goncalo; Willer, Cristen J.; Kathiresan, Sekar; Woo, Daniel; Rosand, JonathanObjective: In observational epidemiologic studies, higher plasma high‐density lipoprotein cholesterol (HDL‐C) has been associated with increased risk of intracerebral hemorrhage (ICH). DNA sequence variants that decrease cholesteryl ester transfer protein (CETP) gene activity increase plasma HDL‐C; as such, medicines that inhibit CETP and raise HDL‐C are in clinical development. Here, we test the hypothesis that CETP DNA sequence variants associated with higher HDL‐C also increase risk for ICH. Methods: We performed 2 candidate‐gene analyses of CETP. First, we tested individual CETP variants in a discovery cohort of 1,149 ICH cases and 1,238 controls from 3 studies, followed by replication in 1,625 cases and 1,845 controls from 5 studies. Second, we constructed a genetic risk score comprised of 7 independent variants at the CETP locus and tested this score for association with HDL‐C as well as ICH risk. Results: Twelve variants within CETP demonstrated nominal association with ICH, with the strongest association at the rs173539 locus (odds ratio [OR] = 1.25, standard error [SE] = 0.06, p = 6.0 × 10−4) with no heterogeneity across studies (I 2 = 0%). This association was replicated in patients of European ancestry (p = 0.03). A genetic score of CETP variants found to increase HDL‐C by ∼2.85mg/dl in the Global Lipids Genetics Consortium was strongly associated with ICH risk (OR = 1.86, SE = 0.13, p = 1.39 × 10−6). Interpretation Genetic variants in CETP associated with increased HDL‐C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL‐raising strategies, further exploration of potential adverse cerebrovascular outcomes may be warranted. Ann Neurol 2016;80:730–740Publication Genetic variation at 16q24.2 is associated with small vessel stroke(John Wiley and Sons Inc., 2017) Traylor, Matthew; Malik, Rainer; Nalls, Mike A.; Cotlarciuc, Ioana; Radmanesh, Farid; Thorleifsson, Gudmar; Hanscombe, Ken B.; Langefeld, Carl; Saleheen, Danish; Rost, Natalia S.; Yet, Idil; Spector, Tim D.; Bell, Jordana T.; Hannon, Eilis; Mill, Jonathan; Chauhan, Ganesh; Debette, Stephanie; Bis, Joshua C.; Longstreth, W.T.; Ikram, M. Arfan; Launer, Lenore J.; Seshadri, Sudha; Hamilton‐Bruce, Monica Anne; Jimenez‐Conde, Jordi; Cole, John W.; Schmidt, Reinhold; Słowik, Agnieszka; Lemmens, Robin; Lindgren, Arne; Melander, Olle; Grewal, Raji P.; Sacco, Ralph L.; Rundek, Tatjana; Rexrode, Kathryn; Arnett, Donna K.; Johnson, Julie A.; Benavente, Oscar R.; Wasssertheil‐Smoller, Sylvia; Lee, Jin‐Moo; Pulit, Sara L.; Wong, Quenna; Rich, Stephen S.; de Bakker, Paul I.W.; McArdle, Patrick F.; Woo, Daniel; Anderson, Christopher; Xu, Huichun; Heitsch, Laura; Fornage, Myriam; Jern, Christina; Stefansson, Kari; Thorsteinsdottir, Unnur; Gretarsdottir, Solveig; Lewis, Cathryn M.; Sharma, Pankaj; Sudlow, Cathie L.M.; Rothwell, Peter M.; Boncoraglio, Giorgio B.; Thijs, Vincent; Levi, Chris; Meschia, James F.; Rosand, Jonathan; Kittner, Steven J.; Mitchell, Braxton D.; Dichgans, Martin; Worrall, Bradford B.; Markus, Hugh S.Objective: Genome‐wide association studies (GWAS) have been successful at identifying associations with stroke and stroke subtypes, but have not yet identified any associations solely with small vessel stroke (SVS). SVS comprises one quarter of all ischemic stroke and is a major manifestation of cerebral small vessel disease, the primary cause of vascular cognitive impairment. Studies across neurological traits have shown that younger‐onset cases have an increased genetic burden. We leveraged this increased genetic burden by performing an age‐at‐onset informed GWAS meta‐analysis, including a large younger‐onset SVS population, to identify novel associations with stroke. Methods: We used a three‐stage age‐at‐onset informed GWAS to identify novel genetic variants associated with stroke. On identifying a novel locus associated with SVS, we assessed its influence on other small vessel disease phenotypes, as well as on messenger RNA (mRNA) expression of nearby genes, and on DNA methylation of nearby CpG sites in whole blood and in the fetal brain. Results: We identified an association with SVS in 4,203 cases and 50,728 controls on chromosome 16q24.2 (odds ratio [OR; 95% confidence interval {CI}] = 1.16 [1.10–1.22]; p = 3.2 × 10−9). The lead single‐nucleotide polymorphism (rs12445022) was also associated with cerebral white matter hyperintensities (OR [95% CI] = 1.10 [1.05–1.16]; p = 5.3 × 10−5; N = 3,670), but not intracerebral hemorrhage (OR [95% CI] = 0.97 [0.84–1.12]; p = 0.71; 1,545 cases, 1,481 controls). rs12445022 is associated with mRNA expression of ZCCHC14 in arterial tissues (p = 9.4 × 10−7) and DNA methylation at probe cg16596957 in whole blood (p = 5.3 × 10−6). Interpretation 16q24.2 is associated with SVS. Associations of the locus with expression of ZCCHC14 and DNA methylation suggest the locus acts through changes to regulatory elements. Ann Neurol 2017;81:383–394Publication Selective Disruption of the Cerebral Neocortex in Alzheimer's Disease(Public Library of Science, 2010) Desikan, Rahul S.; Schmansky, Nicholas J.; Cabral, Howard J.; Hess, Christopher P.; Weiner, Michael W.; Kemper, Thomas L.; Dale, Anders M.; Sabuncu, Mert R; the Alzheimer’s Disease Neuroimaging Initiative; Reuter, Martin; Biffi, Alessandro; Anderson, Christopher; Rosand, Jonathan; Salat, David; Sperling, Reisa; Fischl, BruceBackground: Alzheimer's disease (AD) and its transitional state mild cognitive impairment (MCI) are characterized by amyloid plaque and tau neurofibrillary tangle (NFT) deposition within the cerebral neocortex and neuronal loss within the hippocampal formation. However, the precise relationship between pathologic changes in neocortical regions and hippocampal atrophy is largely unknown. Methodology/Principal Findings: In this study, combining structural MRI scans and automated image analysis tools with reduced cerebrospinal fluid (CSF) Aß levels, a surrogate for intra-cranial amyloid plaques and elevated CSF phosphorylated tau (p-tau) levels, a surrogate for neocortical NFTs, we examined the relationship between the presence of Alzheimer's pathology, gray matter thickness of select neocortical regions, and hippocampal volume in cognitively normal older participants and individuals with MCI and AD (n = 724). Amongst all 3 groups, only select heteromodal cortical regions significantly correlated with hippocampal volume. Amongst MCI and AD individuals, gray matter thickness of the entorhinal cortex and inferior temporal gyrus significantly predicted longitudinal hippocampal volume loss in both amyloid positive and p-tau positive individuals. Amongst cognitively normal older adults, thinning only within the medial portion of the orbital frontal cortex significantly differentiated amyloid positive from amyloid negative individuals whereas thinning only within the entorhinal cortex significantly discriminated p-tau positive from p-tau negative individuals. Conclusions/Significance: Cortical Aβ and tau pathology affects gray matter thinning within select neocortical regions and potentially contributes to downstream hippocampal degeneration. Neocortical Alzheimer's pathology is evident even amongst older asymptomatic individuals suggesting the existence of a preclinical phase of dementia.