@article {6067, title = {Best practices and joint calling of the HumanExome BeadChip: the CHARGE Consortium.}, journal = {PLoS One}, volume = {8}, year = {2013}, month = {2013}, pages = {e68095}, abstract = {

Genotyping arrays are a cost effective approach when typing previously-identified genetic polymorphisms in large numbers of samples. One limitation of genotyping arrays with rare variants (e.g., minor allele frequency [MAF] <0.01) is the difficulty that automated clustering algorithms have to accurately detect and assign genotype calls. Combining intensity data from large numbers of samples may increase the ability to accurately call the genotypes of rare variants. Approximately 62,000 ethnically diverse samples from eleven Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium cohorts were genotyped with the Illumina HumanExome BeadChip across seven genotyping centers. The raw data files for the samples were assembled into a single project for joint calling. To assess the quality of the joint calling, concordance of genotypes in a subset of individuals having both exome chip and exome sequence data was analyzed. After exclusion of low performing SNPs on the exome chip and non-overlap of SNPs derived from sequence data, genotypes of 185,119 variants (11,356 were monomorphic) were compared in 530 individuals that had whole exome sequence data. A total of 98,113,070 pairs of genotypes were tested and 99.77\% were concordant, 0.14\% had missing data, and 0.09\% were discordant. We report that joint calling allows the ability to accurately genotype rare variation using array technology when large sample sizes are available and best practices are followed. The cluster file from this experiment is available at www.chargeconsortium.com/main/exomechip.

}, keywords = {Aging, Alleles, Cluster Analysis, Cohort Studies, Continental Population Groups, Exome, Female, Gene Frequency, Genomics, Genotype, Heart, Humans, Male, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, Sample Size, Self Report, Sequence Analysis, DNA}, issn = {1932-6203}, doi = {10.1371/journal.pone.0068095}, author = {Grove, Megan L and Yu, Bing and Cochran, Barbara J and Haritunians, Talin and Bis, Joshua C and Taylor, Kent D and Hansen, Mark and Borecki, Ingrid B and Cupples, L Adrienne and Fornage, Myriam and Gudnason, Vilmundur and Harris, Tamara B and Kathiresan, Sekar and Kraaij, Robert and Launer, Lenore J and Levy, Daniel and Liu, Yongmei and Mosley, Thomas and Peloso, Gina M and Psaty, Bruce M and Rich, Stephen S and Rivadeneira, Fernando and Siscovick, David S and Smith, Albert V and Uitterlinden, Andre and van Duijn, Cornelia M and Wilson, James G and O{\textquoteright}Donnell, Christopher J and Rotter, Jerome I and Boerwinkle, Eric} } @article {6338, title = {Separate prediction of intracerebral hemorrhage and ischemic stroke.}, journal = {Neurology}, volume = {82}, year = {2014}, month = {2014 May 20}, pages = {1804-12}, abstract = {

OBJECTIVES: To develop and validate 10-year cumulative incidence functions of intracerebral hemorrhage (ICH) and ischemic stroke (IS).

METHODS: We used data on 27,493 participants from 3 population-based cohort studies: the Atherosclerosis Risk in Communities Study, median age 54 years, 45\% male, median follow-up 20.7 years; the Rotterdam Study, median age 68 years, 38\% male, median follow-up 14.3 years; and the Cardiovascular Health Study, median age 71 years, 41\% male, median follow-up 12.8 years. Among these participants, 325 ICH events, 2,559 IS events, and 9,909 nonstroke deaths occurred. We developed 10-year cumulative incidence functions for ICH and IS using stratified Cox regression and competing risks analysis. Basic models including only established nonlaboratory risk factors were extended with diastolic blood pressure, total cholesterol/high-density lipoprotein cholesterol ratio, body mass index, waist-to-hip ratio, and glomerular filtration rate. The cumulative incidence functions{\textquoteright} performances were cross-validated in each cohort separately by Harrell C-statistic and calibration plots.

RESULTS: High total cholesterol/high-density lipoprotein cholesterol ratio decreased the ICH rates but increased IS rates (p for difference across stroke types <0.001). For both the ICH and IS models, C statistics increased more by model extension in the Atherosclerosis Risk in Communities and Cardiovascular Health Study cohorts. Improvements in C statistics were reproduced by cross-validation. Models were well calibrated in all cohorts. Correlations between 10-year ICH and IS risks were moderate in each cohort.

CONCLUSIONS: We developed and cross-validated cumulative incidence functions for separate prediction of 10-year ICH and IS risk. These functions can be useful to further specify an individual{\textquoteright}s stroke risk.

}, keywords = {Aged, Aged, 80 and over, Atherosclerosis, Body Mass Index, Brain Ischemia, Cholesterol, Female, Humans, Incidence, Intracranial Hemorrhages, Male, Middle Aged, Models, Statistical, Predictive Value of Tests, Risk Assessment, Risk Factors, Stroke}, issn = {1526-632X}, doi = {10.1212/WNL.0000000000000427}, author = {Ferket, Bart S and van Kempen, Bob J H and Wieberdink, Renske G and Steyerberg, Ewout W and Koudstaal, Peter J and Hofman, Albert and Shahar, Eyal and Gottesman, Rebecca F and Rosamond, Wayne and Kizer, Jorge R and Kronmal, Richard A and Psaty, Bruce M and Longstreth, W T and Mosley, Thomas and Folsom, Aaron R and Hunink, M G Myriam and Ikram, M Arfan} } @article {7565, title = {Bivariate Genome-Wide Association Study of Depressive Symptoms with Type 2 Diabetes and Quantitative Glycemic Traits.}, journal = {Psychosom Med}, year = {2017}, month = {2017 Dec 27}, abstract = {

OBJECTIVE: Shared genetic background may explain phenotypic associations between depression and Type-2-Diabetes (T2D). We aimed to study, on a genome-wide level, if genetic correlation and pleiotropic loci exist between depressive symptoms and T2D or glycemic traits.

METHODS: We estimated SNP-based heritability and analyzed genetic correlation between depressive symptoms and T2D and glycemic traits with the LD Score Regression (LDSC) by combining summary statistics of previously conducted meta-analyses for depressive symptoms by CHARGE consortium (N = 51,258), T2D by Diagram consortium (N = 34,840 patients and 114,981 controls), fasting glucose, fasting insulin, HOMA-β, and HOMA-IR by MAGIC consortium (N = 58,074). Finally, we investigated pleiotropic loci using a bivariate GWAS approach with summary statistics from GWAS meta-analyses and reported loci with genome-wide significant bivariate association p-value (p < 5x10). Biological annotation and function of significant pleiotropic SNPs were assessed in several databases.

RESULTS: The SNP-based heritability ranged from 0.04 to 0.10 in each individual trait. In the LDSC analyses, depressive symptoms showed no significant genetic correlation with T2D or glycemic traits (p > 0.37). Yet, we identified pleiotropic genetic variations for depressive symptoms and T2D (in the IGF2BP2, CDKAL1, CDKN2B-AS, and PLEKHA1 genes), and fasting glucose (in the MADD, CDKN2B-AS, PEX16, and MTNR1B genes).

CONCLUSIONS: We found no significant overall genetic correlations between depressive symptoms, T2D or glycemic traits suggesting major differences in underlying biology of these traits. Yet, several potential pleiotropic loci were identified between depressive symptoms, T2D and fasting glucose suggesting that previously established phenotypic associations may be partly explained by genetic variation in these specific loci.

}, issn = {1534-7796}, doi = {10.1097/PSY.0000000000000555}, author = {Haljas, Kadri and Amare, Azmeraw T and Alizadeh, Behrooz Z and Hsu, Yi-Hsiang and Mosley, Thomas and Newman, Anne and Murabito, Joanne and Tiemeier, Henning and Tanaka, Toshiko and van Duijn, Cornelia and Ding, Jingzhong and Llewellyn, David J and Bennett, David A and Terracciano, Antonio and Launer, Lenore and Ladwig, Karl-Heinz and Cornelis, Marylin C and Teumer, Alexander and Grabe, Hans and Kardia, Sharon L R and Ware, Erin B and Smith, Jennifer A and Snieder, Harold and Eriksson, Johan G and Groop, Leif and R{\"a}ikk{\"o}nen, Katri and Lahti, Jari} } @article {7554, title = {Trends in the incidence of dementia: design and methods in the Alzheimer Cohorts Consortium.}, journal = {Eur J Epidemiol}, volume = {32}, year = {2017}, month = {2017 Oct}, pages = {931-938}, abstract = {

Several studies have reported a decline in incidence of dementia which may have large implications for the projected burden of disease, and provide important guidance to preventive efforts. However, reports are conflicting or inconclusive with regard to the impact of gender and education with underlying causes of a presumed declining trend remaining largely unidentified. The Alzheimer Cohorts Consortium aggregates data from nine international population-based cohorts to determine changes in the incidence of dementia since 1990. We will employ Poisson regression models to calculate incidence rates in each cohort and Cox proportional hazard regression to compare 5-year cumulative hazards across study-specific epochs. Finally, we will meta-analyse changes per decade across cohorts, and repeat all analysis stratified by sex, education and APOE genotype. In all cohorts combined, there are data on almost 69,000 people at risk of dementia with the range of follow-up years between 2 and 27. The average age at baseline is similar across cohorts ranging between 72 and 77. Uniting a wide range of disease-specific and methodological expertise in research teams, the first analyses within the Alzheimer Cohorts Consortium are underway to tackle outstanding challenges in the assessment of time-trends in dementia occurrence.

}, issn = {1573-7284}, doi = {10.1007/s10654-017-0320-5}, author = {Chibnik, Lori B and Wolters, Frank J and B{\"a}ckman, Kristoffer and Beiser, Alexa and Berr, Claudine and Bis, Joshua C and Boerwinkle, Eric and Bos, Daniel and Brayne, Carol and Dartigues, Jean-Fran{\c c}ois and Darweesh, Sirwan K L and Debette, Stephanie and Davis-Plourde, Kendra L and Dufouil, Carole and Fornage, Myriam and Grasset, Leslie and Gudnason, Vilmundur and Hadjichrysanthou, Christoforos and Helmer, Catherine and Ikram, M Arfan and Ikram, M Kamran and Kern, Silke and Kuller, Lewis H and Launer, Lenore and Lopez, Oscar L and Matthews, Fiona and Meirelles, Osorio and Mosley, Thomas and Ower, Alison and Psaty, Bruce M and Satizabal, Claudia L and Seshadri, Sudha and Skoog, Ingmar and Stephan, Blossom C M and Tzourio, Christophe and Waziry, Reem and Wong, Mei Mei and Zettergren, Anna and Hofman, Albert} } @article {9163, title = {Associations of Pulmonary Function with MRI Brain Volumes: A Coordinated Multi-Study Analysis.}, journal = {J Alzheimers Dis}, year = {2022}, month = {2022 Oct 03}, abstract = {

BACKGROUND: Previous studies suggest poor pulmonary function is associated with increased burden of cerebral white matter hyperintensities and brain atrophy among elderly individuals, but the results are inconsistent.

OBJECTIVE: To study the cross-sectional associations of pulmonary function with structural brain variables.

METHODS: Data from six large community-based samples (N = 11,091) were analyzed. Spirometric measurements were standardized with respect to age, sex, height, and ethnicity using reference equations of the Global Lung Function Initiative. Associations of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and their ratio FEV1/FVC with brain volume, gray matter volume, hippocampal volume, and volume of white matter hyperintensities were investigated using multivariable linear regressions for each study separately and then combined using random-effect meta-analyses.

RESULTS: FEV1 and FVC were positively associated with brain volume, gray matter volume, and hippocampal volume, and negatively associated with white matter hyperintensities volume after multiple testing correction, with little heterogeneity present between the studies. For instance, an increase of FVC by one unit was associated with 3.5 ml higher brain volume (95\% CI: [2.2, 4.9]). In contrast, results for FEV1/FVC were more heterogeneous across studies, with significant positive associations with brain volume, gray matter volume, and hippocampal volume, but not white matter hyperintensities volume. Associations of brain variables with both FEV1 and FVC were consistently stronger than with FEV1/FVC, specifically with brain volume and white matter hyperintensities volume.

CONCLUSION: In cross-sectional analyses, worse pulmonary function is associated with smaller brain volumes and higher white matter hyperintensities burden.

}, issn = {1875-8908}, doi = {10.3233/JAD-220667}, author = {Frenzel, Stefan and Bis, Josh C and Gudmundsson, Elias F and O{\textquoteright}Donnell, Adrienne and Simino, Jeannette and Yaqub, Amber and Bartz, Traci M and Brusselle, Guy G O and B{\"u}low, Robin and DeCarli, Charles S and Ewert, Ralf and Gharib, Sina A and Ghosh, Saptaparni and Gireud-Goss, Monica and Gottesman, Rebecca F and Ikram, M Arfan and Knopman, David S and Launer, Lenore J and London, Stephanie J and Longstreth, W T and Lopez, Oscar L and Melo van Lent, Debora and O{\textquoteright}Connor, George and Satizabal, Claudia L and Shrestha, Srishti and Sigurdsson, Sigurdur and Stubbe, Beate and Talluri, Rajesh and Vasan, Ramachandran S and Vernooij, Meike W and V{\"o}lzke, Henry and Wiggins, Kerri L and Yu, Bing and Beiser, Alexa S and Gudnason, Vilmundur and Mosley, Thomas and Psaty, Bruce M and Wolters, Frank J and Grabe, Hans J and Seshadri, Sudha} } @article {9035, title = {New insights into the genetic etiology of Alzheimer{\textquoteright}s disease and related dementias.}, journal = {Nat Genet}, volume = {54}, year = {2022}, month = {2022 Apr}, pages = {412-436}, abstract = {

Characterization of the genetic landscape of Alzheimer{\textquoteright}s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/{\textquoteright}proxy{\textquoteright} AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

}, keywords = {Alzheimer Disease, Cognitive Dysfunction, Genome-Wide Association Study, Humans, tau Proteins}, issn = {1546-1718}, doi = {10.1038/s41588-022-01024-z}, author = {Bellenguez, C{\'e}line and K{\"u}{\c c}{\"u}kali, Fahri and Jansen, Iris E and Kleineidam, Luca and Moreno-Grau, Sonia and Amin, Najaf and Naj, Adam C and Campos-Martin, Rafael and Grenier-Boley, Benjamin and Andrade, Victor and Holmans, Peter A and Boland, Anne and Damotte, Vincent and van der Lee, Sven J and Costa, Marcos R and Kuulasmaa, Teemu and Yang, Qiong and de Rojas, Itziar and Bis, Joshua C and Yaqub, Amber and Prokic, Ivana and Chapuis, Julien and Ahmad, Shahzad and Giedraitis, Vilmantas and Aarsland, Dag and Garcia-Gonzalez, Pablo and Abdelnour, Carla and Alarc{\'o}n-Mart{\'\i}n, Emilio and Alcolea, Daniel and Alegret, Montserrat and Alvarez, Ignacio and Alvarez, Victoria and Armstrong, Nicola J and Tsolaki, Anthoula and Antunez, Carmen and Appollonio, Ildebrando and Arcaro, Marina and Archetti, Silvana and Pastor, Alfonso Arias and Arosio, Beatrice and Athanasiu, Lavinia and Bailly, Henri and Banaj, Nerisa and Baquero, Miquel and Barral, Sandra and Beiser, Alexa and Pastor, Ana Bel{\'e}n and Below, Jennifer E and Benchek, Penelope and Benussi, Luisa and Berr, Claudine and Besse, C{\'e}line and Bessi, Valentina and Binetti, Giuliano and Bizarro, Alessandra and Blesa, Rafael and Boada, Merce and Boerwinkle, Eric and Borroni, Barbara and Boschi, Silvia and Boss{\`u}, Paola and Br{\r a}then, Geir and Bressler, Jan and Bresner, Catherine and Brodaty, Henry and Brookes, Keeley J and Brusco, Luis Ignacio and Buiza-Rueda, Dolores and B{\^u}rger, Katharina and Burholt, Vanessa and Bush, William S and Calero, Miguel and Cantwell, Laura B and Chene, Genevi{\`e}ve and Chung, Jaeyoon and Cuccaro, Michael L and Carracedo, Angel and Cecchetti, Roberta and Cervera-Carles, Laura and Charbonnier, Camille and Chen, Hung-Hsin and Chillotti, Caterina and Ciccone, Simona and Claassen, Jurgen A H R and Clark, Christopher and Conti, Elisa and Corma-G{\'o}mez, Ana{\"\i}s and Costantini, Emanuele and Custodero, Carlo and Daian, Delphine and Dalmasso, Maria Carolina and Daniele, Antonio and Dardiotis, Efthimios and Dartigues, Jean-Fran{\c c}ois and de Deyn, Peter Paul and de Paiva Lopes, Katia and de Witte, Lot D and Debette, Stephanie and Deckert, J{\"u}rgen and Del Ser, Teodoro and Denning, Nicola and DeStefano, Anita and Dichgans, Martin and Diehl-Schmid, Janine and Diez-Fairen, Monica and Rossi, Paolo Dionigi and Djurovic, Srdjan and Duron, Emmanuelle and D{\"u}zel, Emrah and Dufouil, Carole and Eiriksdottir, Gudny and Engelborghs, Sebastiaan and Escott-Price, Valentina and Espinosa, Ana and Ewers, Michael and Faber, Kelley M and Fabrizio, Tagliavini and Nielsen, Sune Fallgaard and Fardo, David W and Farotti, Lucia and Fenoglio, Chiara and Fern{\'a}ndez-Fuertes, Marta and Ferrari, Raffaele and Ferreira, Catarina B and Ferri, Evelyn and Fin, Bertrand and Fischer, Peter and Fladby, Tormod and Flie{\ss}bach, Klaus and Fongang, Bernard and Fornage, Myriam and Fortea, Juan and Foroud, Tatiana M and Fostinelli, Silvia and Fox, Nick C and Franco-Mac{\'\i}as, Emlio and Bullido, Mar{\'\i}a J and Frank-Garc{\'\i}a, Ana and Froelich, Lutz and Fulton-Howard, Brian and Galimberti, Daniela and Garc{\'\i}a-Alberca, Jose Maria and Garcia-Gonzalez, Pablo and Garcia-Madrona, Sebastian and Garcia-Ribas, Guillermo and Ghidoni, Roberta and Giegling, Ina and Giorgio, Giaccone and Goate, Alison M and Goldhardt, Oliver and Gomez-Fonseca, Duber and Gonz{\'a}lez-Perez, Antonio and Graff, Caroline and Grande, Giulia and Green, Emma and Grimmer, Timo and Gr{\"u}nblatt, Edna and Grunin, Michelle and Gudnason, Vilmundur and Guetta-Baranes, Tamar and Haapasalo, Annakaisa and Hadjigeorgiou, Georgios and Haines, Jonathan L and Hamilton-Nelson, Kara L and Hampel, Harald and Hanon, Olivier and Hardy, John and Hartmann, Annette M and Hausner, Lucrezia and Harwood, Janet and Heilmann-Heimbach, Stefanie and Helisalmi, Seppo and Heneka, Michael T and Hernandez, Isabel and Herrmann, Martin J and Hoffmann, Per and Holmes, Clive and Holstege, Henne and Vilas, Raquel Huerto and Hulsman, Marc and Humphrey, Jack and Biessels, Geert Jan and Jian, Xueqiu and Johansson, Charlotte and Jun, Gyungah R and Kastumata, Yuriko and Kauwe, John and Kehoe, Patrick G and Kilander, Lena and St{\r a}hlbom, Anne Kinhult and Kivipelto, Miia and Koivisto, Anne and Kornhuber, Johannes and Kosmidis, Mary H and Kukull, Walter A and Kuksa, Pavel P and Kunkle, Brian W and Kuzma, Amanda B and Lage, Carmen and Laukka, Erika J and Launer, Lenore and Lauria, Alessandra and Lee, Chien-Yueh and Lehtisalo, Jenni and Lerch, Ondrej and Lleo, Alberto and Longstreth, William and Lopez, Oscar and de Munain, Adolfo Lopez and Love, Seth and L{\"o}wemark, Malin and Luckcuck, Lauren and Lunetta, Kathryn L and Ma, Yiyi and Mac{\'\i}as, Juan and MacLeod, Catherine A and Maier, Wolfgang and Mangialasche, Francesca and Spallazzi, Marco and Marqui{\'e}, Marta and Marshall, Rachel and Martin, Eden R and Montes, Angel Mart{\'\i}n and Rodr{\'\i}guez, Carmen Mart{\'\i}nez and Masullo, Carlo and Mayeux, Richard and Mead, Simon and Mecocci, Patrizia and Medina, Miguel and Meggy, Alun and Mehrabian, Shima and Mendoza, Silvia and Men{\'e}ndez-Gonz{\'a}lez, Manuel and Mir, Pablo and Moebus, Susanne and Mol, Merel and Molina-Porcel, Laura and Montrreal, Laura and Morelli, Laura and Moreno, Fermin and Morgan, Kevin and Mosley, Thomas and N{\"o}then, Markus M and Muchnik, Carolina and Mukherjee, Shubhabrata and Nacmias, Benedetta and Ngandu, Tiia and Nicolas, Ga{\"e}l and Nordestgaard, B{\o}rge G and Olaso, Robert and Orellana, Adelina and Orsini, Michela and Ortega, Gemma and Padovani, Alessandro and Paolo, Caffarra and Papenberg, Goran and Parnetti, Lucilla and Pasquier, Florence and Pastor, Pau and Peloso, Gina and P{\'e}rez-Cord{\'o}n, Alba and P{\'e}rez-Tur, Jordi and Pericard, Pierre and Peters, Oliver and Pijnenburg, Yolande A L and Pineda, Juan A and Pi{\~n}ol-Ripoll, Gerard and Pisanu, Claudia and Polak, Thomas and Popp, Julius and Posthuma, Danielle and Priller, Josef and Puerta, Raquel and Quenez, Olivier and Quintela, In{\'e}s and Thomassen, Jesper Qvist and R{\'a}bano, Alberto and Rainero, Innocenzo and Rajabli, Farid and Ramakers, Inez and Real, Luis M and Reinders, Marcel J T and Reitz, Christiane and Reyes-Dumeyer, Dolly and Ridge, Perry and Riedel-Heller, Steffi and Riederer, Peter and Roberto, Natalia and Rodriguez-Rodriguez, Eloy and Rongve, Arvid and Allende, Irene Rosas and Rosende-Roca, Mait{\'e}e and Royo, Jose Luis and Rubino, Elisa and Rujescu, Dan and S{\'a}ez, Mar{\'\i}a Eugenia and Sakka, Paraskevi and Saltvedt, Ingvild and Sanabria, {\'A}ngela and S{\'a}nchez-Arjona, Mar{\'\i}a Bernal and Sanchez-Garcia, Florentino and Juan, Pascual S{\'a}nchez and S{\'a}nchez-Valle, Raquel and Sando, Sigrid B and Sarnowski, Chloe and Satizabal, Claudia L and Scamosci, Michela and Scarmeas, Nikolaos and Scarpini, Elio and Scheltens, Philip and Scherbaum, Norbert and Scherer, Martin and Schmid, Matthias and Schneider, Anja and Schott, Jonathan M and Selb{\ae}k, Geir and Seripa, Davide and Serrano, Manuel and Sha, Jin and Shadrin, Alexey A and Skrobot, Olivia and Slifer, Susan and Snijders, Gijsje J L and Soininen, Hilkka and Solfrizzi, Vincenzo and Solomon, Alina and Song, Yeunjoo and Sorbi, Sandro and Sotolongo-Grau, Oscar and Spalletta, Gianfranco and Spottke, Annika and Squassina, Alessio and Stordal, Eystein and Tartan, Juan Pablo and Tarraga, Lluis and Tes{\'\i}, Niccolo and Thalamuthu, Anbupalam and Thomas, Tegos and Tosto, Giuseppe and Traykov, Latchezar and Tremolizzo, Lucio and Tybj{\ae}rg-Hansen, Anne and Uitterlinden, Andre and Ullgren, Abbe and Ulstein, Ingun and Valero, Sergi and Valladares, Otto and Broeckhoven, Christine Van and Vance, Jeffery and Vardarajan, Badri N and van der Lugt, Aad and Dongen, Jasper Van and van Rooij, Jeroen and van Swieten, John and Vandenberghe, Rik and Verhey, Frans and Vidal, Jean-S{\'e}bastien and Vogelgsang, Jonathan and Vyhnalek, Martin and Wagner, Michael and Wallon, David and Wang, Li-San and Wang, Ruiqi and Weinhold, Leonie and Wiltfang, Jens and Windle, Gill and Woods, Bob and Yannakoulia, Mary and Zare, Habil and Zhao, Yi and Zhang, Xiaoling and Zhu, Congcong and Zulaica, Miren and Farrer, Lindsay A and Psaty, Bruce M and Ghanbari, Mohsen and Raj, Towfique and Sachdev, Perminder and Mather, Karen and Jessen, Frank and Ikram, M Arfan and de Mendon{\c c}a, Alexandre and Hort, Jakub and Tsolaki, Magda and Pericak-Vance, Margaret A and Amouyel, Philippe and Williams, Julie and Frikke-Schmidt, Ruth and Clarimon, Jordi and Deleuze, Jean-Francois and Rossi, Giacomina and Seshadri, Sudha and Andreassen, Ole A and Ingelsson, Martin and Hiltunen, Mikko and Sleegers, Kristel and Schellenberg, Gerard D and van Duijn, Cornelia M and Sims, Rebecca and van der Flier, Wiesje M and Ruiz, Agustin and Ramirez, Alfredo and Lambert, Jean-Charles} } @article {9781, title = {Plasma proteome-wide analysis of cerebral small vessel disease identifies novel biomarkers and disease pathways.}, journal = {medRxiv}, year = {2024}, month = {2024 Oct 08}, abstract = {

Cerebral small vessel disease (SVD), as defined by neuroimaging characteristics such as white matter hyperintensities (WMHs), cerebral microhemorrhages (CMHs), and lacunar infarcts, is highly prevalent and has been associated with dementia risk and other clinical sequelae. Although conditions such as hypertension are known to contribute to SVD, little is known about the diverse set of subclinical biological processes and molecular mediators that may also influence the development and progression of SVD. To better understand the mechanisms underlying SVD and to identify novel SVD biomarkers, we used a large-scale proteomic platform to relate 4,877 plasma proteins to MRI-defined SVD characteristics within 1,508 participants of the Atherosclerosis Risk in Communities (ARIC) Study cohort. Our proteome-wide analysis of older adults (mean age: 76) identified 13 WMH-associated plasma proteins involved in synaptic function, endothelial integrity, and angiogenesis, two of which remained associated with late-life WMH volume when measured nearly 20 years earlier, during midlife. We replicated the relationship between 9 candidate proteins and WMH volume in one or more external cohorts; we found that 11 of the 13 proteins were associated with risk for future dementia; and we leveraged publicly available proteomic data from brain tissue to demonstrate that a subset of WMH-associated proteins was differentially expressed in the context of cerebral atherosclerosis, pathologically-defined Alzheimer{\textquoteright}s disease, and cognitive decline. Bidirectional two-sample Mendelian randomization analyses examined the causal relationships between candidate proteins and WMH volume, while pathway and network analyses identified discrete biological processes (lipid/cholesterol metabolism, NF-kB signaling, hemostasis) associated with distinct forms of SVD. Finally, we synthesized these findings to identify two plasma proteins, oligodendrocyte myelin glycoprotein (OMG) and neuronal pentraxin receptor (NPTXR), as top candidate biomarkers for elevated WMH volume and its clinical manifestations.

}, doi = {10.1101/2024.10.07.24314972}, author = {Gomez, Gabriela T and Shi, Liu and Fohner, Alison E and Chen, Jingsha and Yang, Yunju and Fornage, Myriam and Duggan, Michael R and Peng, Zhongsheng and Daya, Gulzar N and Tin, Adrienne and Schlosser, Pascal and Longstreth, W T and Kalani, Rizwan and Sharma, Malveeka and Psaty, Bruce M and Nevado-Holgado, Alejo J and Buckley, Noel J and Gottesman, Rebecca F and Lutsey, Pamela L and Jack, Clifford R and Sullivan, Kevin J and Mosley, Thomas and Hughes, Timothy M and Coresh, Josef and Walker, Keenan A} }