@article {1092, title = {Genomewide association studies of stroke.}, journal = {N Engl J Med}, volume = {360}, year = {2009}, month = {2009 Apr 23}, pages = {1718-28}, abstract = {

BACKGROUND: The genes underlying the risk of stroke in the general population remain undetermined.

METHODS: We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [+/-SD] age, 63+/-8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons.

RESULTS: Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P<5x10(-8)). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95\% confidence interval [CI], 1.19 to 1.42) and 1.33 (95\% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11\% and 12\% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95\% CI, 1.01 to 1.79; P=0.04) and 1.42 (95\% CI, 1.06 to 1.91; P=0.02) in the large cohort of black persons and 1.17 (95\% CI, 1.01 to 1.37; P=0.03) and 1.19 (95\% CI, 1.01 to 1.41; P=0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant.

CONCLUSIONS: A genetic locus on chromosome 12p13 is associated with an increased risk of stroke.

}, keywords = {African Continental Ancestry Group, Aged, Chromosomes, Human, Pair 12, Cohort Studies, European Continental Ancestry Group, Female, Genetic Markers, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Proportional Hazards Models, Risk Factors, Stroke}, issn = {1533-4406}, doi = {10.1056/NEJMoa0900094}, author = {Ikram, M Arfan and Seshadri, Sudha and Bis, Joshua C and Fornage, Myriam and DeStefano, Anita L and Aulchenko, Yurii S and Debette, Stephanie and Lumley, Thomas and Folsom, Aaron R and van den Herik, Evita G and Bos, Michiel J and Beiser, Alexa and Cushman, Mary and Launer, Lenore J and Shahar, Eyal and Struchalin, Maksim and Du, Yangchun and Glazer, Nicole L and Rosamond, Wayne D and Rivadeneira, Fernando and Kelly-Hayes, Margaret and Lopez, Oscar L and Coresh, Josef and Hofman, Albert and DeCarli, Charles and Heckbert, Susan R and Koudstaal, Peter J and Yang, Qiong and Smith, Nicholas L and Kase, Carlos S and Rice, Kenneth and Haritunians, Talin and Roks, Gerwin and de Kort, Paul L M and Taylor, Kent D and de Lau, Lonneke M and Oostra, Ben A and Uitterlinden, Andr{\'e} G and Rotter, Jerome I and Boerwinkle, Eric and Psaty, Bruce M and Mosley, Thomas H and van Duijn, Cornelia M and Breteler, Monique M B and Longstreth, W T and Wolf, Philip A} } @article {1156, title = {Genome-wide association studies of MRI-defined brain infarcts: meta-analysis from the CHARGE Consortium.}, journal = {Stroke}, volume = {41}, year = {2010}, month = {2010 Feb}, pages = {210-7}, abstract = {

BACKGROUND AND PURPOSE: Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.

METHODS: Using 2.2 million genotyped and imputed single nucleotide polymorphisms, each study performed cross-sectional genome-wide association analysis of MRI infarct using age- and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance-weighted meta-analysis, including 9401 participants with mean age 69.7 (19.4\% of whom had >or=1 MRI infarct).

RESULTS: The most significant association was found with rs2208454 (minor allele frequency, 20\%), located in intron 3 of MACRO domain containing 2 gene and in the downstream region of fibronectin leucine-rich transmembrane protein 3 gene. Each copy of the minor allele was associated with lower risk of MRI infarcts (odds ratio, 0.76; 95\% confidence interval, 0.68-0.84; P=4.64x10(-7)). Highly suggestive associations (P<1.0x10(-5)) were also found for 22 other single nucleotide polymorphisms in linkage disequilibrium (r(2)>0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 black participants, although 4 single nucleotide polymorphisms within 200 kb from rs2208454 were associated with MRI infarcts in the black population sample.

CONCLUSIONS: This first community-based, genome-wide association study on covert MRI infarcts uncovered novel associations. Although replication of the association with top single nucleotide polymorphisms failed, possibly because of insufficient power, results in the black population sample are encouraging, and further efforts at replication are needed.

}, keywords = {African Americans, Aged, Brain, Brain Infarction, Cohort Studies, DNA Mutational Analysis, Female, Gene Frequency, Genetic Markers, Genetic Predisposition to Disease, Genetic Testing, Genetic Variation, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Magnetic Resonance Imaging, Male, Middle Aged, Polymorphism, Single Nucleotide, Prospective Studies}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.109.569194}, author = {Debette, Stephanie and Bis, Joshua C and Fornage, Myriam and Schmidt, Helena and Ikram, M Arfan and Sigurdsson, Sigurdur and Heiss, Gerardo and Struchalin, Maksim and Smith, Albert V and van der Lugt, Aad and DeCarli, Charles and Lumley, Thomas and Knopman, David S and Enzinger, Christian and Eiriksdottir, Gudny and Koudstaal, Peter J and DeStefano, Anita L and Psaty, Bruce M and Dufouil, Carole and Catellier, Diane J and Fazekas, Franz and Aspelund, Thor and Aulchenko, Yurii S and Beiser, Alexa and Rotter, Jerome I and Tzourio, Christophe and Shibata, Dean K and Tscherner, Maria and Harris, Tamara B and Rivadeneira, Fernando and Atwood, Larry D and Rice, Kenneth and Gottesman, Rebecca F and van Buchem, Mark A and Uitterlinden, Andr{\'e} G and Kelly-Hayes, Margaret and Cushman, Mary and Zhu, Yicheng and Boerwinkle, Eric and Gudnason, Vilmundur and Hofman, Albert and Romero, Jose R and Lopez, Oscar and van Duijn, Cornelia M and Au, Rhoda and Heckbert, Susan R and Wolf, Philip A and Mosley, Thomas H and Seshadri, Sudha and Breteler, Monique M B and Schmidt, Reinhold and Launer, Lenore J and Longstreth, W T} } @article {1298, title = {Genome-wide association studies of cerebral white matter lesion burden: the CHARGE consortium.}, journal = {Ann Neurol}, volume = {69}, year = {2011}, month = {2011 Jun}, pages = {928-39}, abstract = {

OBJECTIVE: White matter hyperintensities (WMHs) detectable by magnetic resonance imaging are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMHs are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified.

METHODS: We performed a meta-analysis of genome-wide association studies (GWASs) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts.

RESULTS: We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs) in 1 locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (p(discovery) = 4.0 {\texttimes} 10(-9) ; p(replication) = 1.3 {\texttimes} 10(-7) ; p(combined) = 4.0 {\texttimes} 10(-15) ). Other SNPs in this region also reaching genome-wide significance were rs9894383 (p = 5.3 {\texttimes} 10(-9) ), rs11869977 (p = 5.7 {\texttimes} 10(-9) ), rs936393 (p = 6.8 {\texttimes} 10(-9) ), rs3744017 (p = 7.3 {\texttimes} 10(-9) ), and rs1055129 (p = 4.1 {\texttimes} 10(-8) ). Variant alleles at these loci conferred a small increase in WMH burden (4-8\% of the overall mean WMH burden in the sample).

INTERPRETATION: This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH.

}, keywords = {Aged, Aged, 80 and over, Cerebral Cortex, Chromosomes, Human, Pair 17, Cognition Disorders, Cohort Studies, European Continental Ancestry Group, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Leukoencephalopathies, Magnetic Resonance Imaging, Male, Middle Aged, Movement Disorders, Nerve Fibers, Myelinated, Polymorphism, Single Nucleotide, Residence Characteristics, RNA, Messenger}, issn = {1531-8249}, doi = {10.1002/ana.22403}, author = {Fornage, Myriam and Debette, Stephanie and Bis, Joshua C and Schmidt, Helena and Ikram, M Arfan and Dufouil, Carole and Sigurdsson, Sigurdur and Lumley, Thomas and DeStefano, Anita L and Fazekas, Franz and Vrooman, Henri A and Shibata, Dean K and Maillard, Pauline and Zijdenbos, Alex and Smith, Albert V and Gudnason, Haukur and de Boer, Renske and Cushman, Mary and Mazoyer, Bernard and Heiss, Gerardo and Vernooij, Meike W and Enzinger, Christian and Glazer, Nicole L and Beiser, Alexa and Knopman, David S and Cavalieri, Margherita and Niessen, Wiro J and Harris, Tamara B and Petrovic, Katja and Lopez, Oscar L and Au, Rhoda and Lambert, Jean-Charles and Hofman, Albert and Gottesman, Rebecca F and Garcia, Melissa and Heckbert, Susan R and Atwood, Larry D and Catellier, Diane J and Uitterlinden, Andr{\'e} G and Yang, Qiong and Smith, Nicholas L and Aspelund, Thor and Romero, Jose R and Rice, Kenneth and Taylor, Kent D and Nalls, Michael A and Rotter, Jerome I and Sharrett, Richey and van Duijn, Cornelia M and Amouyel, Philippe and Wolf, Philip A and Gudnason, Vilmundur and van der Lugt, Aad and Boerwinkle, Eric and Psaty, Bruce M and Seshadri, Sudha and Tzourio, Christophe and Breteler, Monique M B and Mosley, Thomas H and Schmidt, Reinhold and Longstreth, W T and DeCarli, Charles and Launer, Lenore J} } @article {6220, title = {Predicting stroke through genetic risk functions: the CHARGE Risk Score Project.}, journal = {Stroke}, volume = {45}, year = {2014}, month = {2014 Feb}, pages = {403-12}, abstract = {

BACKGROUND AND PURPOSE: Beyond the Framingham Stroke Risk Score, prediction of future stroke may improve with a genetic risk score (GRS) based on single-nucleotide polymorphisms associated with stroke and its risk factors.

METHODS: The study includes 4 population-based cohorts with 2047 first incident strokes from 22,720 initially stroke-free European origin participants aged >=55 years, who were followed for up to 20 years. GRSs were constructed with 324 single-nucleotide polymorphisms implicated in stroke and 9 risk factors. The association of the GRS to first incident stroke was tested using Cox regression; the GRS predictive properties were assessed with area under the curve statistics comparing the GRS with age and sex, Framingham Stroke Risk Score models, and reclassification statistics. These analyses were performed per cohort and in a meta-analysis of pooled data. Replication was sought in a case-control study of ischemic stroke.

RESULTS: In the meta-analysis, adding the GRS to the Framingham Stroke Risk Score, age and sex model resulted in a significant improvement in discrimination (all stroke: Δjoint area under the curve=0.016, P=2.3{\texttimes}10(-6); ischemic stroke: Δjoint area under the curve=0.021, P=3.7{\texttimes}10(-7)), although the overall area under the curve remained low. In all the studies, there was a highly significantly improved net reclassification index (P<10(-4)).

CONCLUSIONS: The single-nucleotide polymorphisms associated with stroke and its risk factors result only in a small improvement in prediction of future stroke compared with the classical epidemiological risk factors for stroke.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Area Under Curve, Case-Control Studies, Cohort Studies, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Regression Analysis, Risk Factors, ROC Curve, Sex Factors, Stroke}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.113.003044}, author = {Ibrahim-Verbaas, Carla A and Fornage, Myriam and Bis, Joshua C and Choi, Seung Hoan and Psaty, Bruce M and Meigs, James B and Rao, Madhu and Nalls, Mike and Fontes, Jo{\~a}o D and O{\textquoteright}Donnell, Christopher J and Kathiresan, Sekar and Ehret, Georg B and Fox, Caroline S and Malik, Rainer and Dichgans, Martin and Schmidt, Helena and Lahti, Jari and Heckbert, Susan R and Lumley, Thomas and Rice, Kenneth and Rotter, Jerome I and Taylor, Kent D and Folsom, Aaron R and Boerwinkle, Eric and Rosamond, Wayne D and Shahar, Eyal and Gottesman, Rebecca F and Koudstaal, Peter J and Amin, Najaf and Wieberdink, Renske G and Dehghan, Abbas and Hofman, Albert and Uitterlinden, Andr{\'e} G and DeStefano, Anita L and Debette, Stephanie and Xue, Luting and Beiser, Alexa and Wolf, Philip A and DeCarli, Charles and Ikram, M Arfan and Seshadri, Sudha and Mosley, Thomas H and Longstreth, W T and van Duijn, Cornelia M and Launer, Lenore J} } @article {6815, title = {Association of Alzheimer{\textquoteright}s disease GWAS loci with MRI markers of brain aging.}, journal = {Neurobiol Aging}, volume = {36}, year = {2015}, month = {2015 Apr}, pages = {1765.e7-16}, abstract = {

Whether novel risk variants of Alzheimer{\textquoteright}s disease (AD) identified through genome-wide association studies also influence magnetic resonance imaging-based intermediate phenotypes of AD in the general population is unclear. We studied association of 24 AD risk loci with intracranial volume, total brain volume, hippocampal volume (HV), white matter hyperintensity burden, and brain infarcts in a meta-analysis of genetic association studies from large population-based samples (N = 8175-11,550). In single-SNP based tests, AD risk allele of APOE (rs2075650) was associated with smaller HV (p = 0.0054) and CD33 (rs3865444) with smaller intracranial volume (p = 0.0058). In gene-based tests, there was associations of HLA-DRB1 with total brain volume (p = 0.0006) and BIN1 with HV (p = 0.00089). A weighted AD genetic risk score was associated with smaller HV (beta {\textpm} SE = -0.047 {\textpm} 0.013, p = 0.00041), even after excluding the APOE locus (p = 0.029). However, only association of AD genetic risk score with HV, including APOE, was significant after multiple testing correction (including number of independent phenotypes tested). These results suggest that novel AD genetic risk variants may contribute to structural brain aging in nondemented older community persons.

}, keywords = {Aging, Alleles, Alzheimer Disease, Apolipoproteins E, Brain, Female, Genome-Wide Association Study, Hippocampus, Humans, Magnetic Resonance Imaging, Male, Organ Size, Polymorphism, Single Nucleotide, Risk, Sialic Acid Binding Ig-like Lectin 3}, issn = {1558-1497}, doi = {10.1016/j.neurobiolaging.2014.12.028}, author = {Chauhan, Ganesh and Adams, Hieab H H and Bis, Joshua C and Weinstein, Galit and Yu, Lei and T{\"o}glhofer, Anna Maria and Smith, Albert Vernon and van der Lee, Sven J and Gottesman, Rebecca F and Thomson, Russell and Wang, Jing and Yang, Qiong and Niessen, Wiro J and Lopez, Oscar L and Becker, James T and Phan, Thanh G and Beare, Richard J and Arfanakis, Konstantinos and Fleischman, Debra and Vernooij, Meike W and Mazoyer, Bernard and Schmidt, Helena and Srikanth, Velandai and Knopman, David S and Jack, Clifford R and Amouyel, Philippe and Hofman, Albert and DeCarli, Charles and Tzourio, Christophe and van Duijn, Cornelia M and Bennett, David A and Schmidt, Reinhold and Longstreth, William T and Mosley, Thomas H and Fornage, Myriam and Launer, Lenore J and Seshadri, Sudha and Ikram, M Arfan and Debette, Stephanie} } @article {6861, title = {White Matter Lesion Progression: Genome-Wide Search for Genetic Influences.}, journal = {Stroke}, volume = {46}, year = {2015}, month = {2015 Nov}, pages = {3048-57}, abstract = {

BACKGROUND AND PURPOSE: White matter lesion (WML) progression on magnetic resonance imaging is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.

METHODS: Heritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from 10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in 7 cohorts risk models including demographics, vascular risk factors plus single-nucleotide polymorphisms that have been shown to be associated cross-sectionally with WML in the current and previous association studies.

RESULTS: A total of 1085 subjects showed WML progression. The heritability estimate for WML progression was low at 6.5\%, and no single-nucleotide polymorphisms achieved genome-wide significance (P<5{\texttimes}10(-8)). Four loci were suggestive (P<1{\texttimes}10(-5)) of an association with WML progression: 10q24.32 (rs10883817, P=1.46{\texttimes}10(-6)); 12q13.13 (rs4761974, P=8.71{\texttimes}10(-7)); 20p12.1 (rs6135309, P=3.69{\texttimes}10(-6)); and 4p15.31 (rs7664442, P=2.26{\texttimes}10(-6)). Variants that have been previously related to WML explained only 0.8\% to 11.7\% more of the variance in WML progression than age, vascular risk factors, and baseline WML burden.

CONCLUSIONS: Common genetic factors contribute little to the progression of age-related WML in middle-aged and older adults. Future research on determinants of WML progression should focus more on environmental, lifestyle, or host-related biological factors.

}, keywords = {Adult, Aged, Cohort Studies, Disease Progression, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Leukoencephalopathies, Male, Middle Aged, Prospective Studies, White Matter}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.115.009252}, author = {Hofer, Edith and Cavalieri, Margherita and Bis, Joshua C and DeCarli, Charles and Fornage, Myriam and Sigurdsson, Sigurdur and Srikanth, Velandai and Trompet, Stella and Verhaaren, Benjamin F J and Wolf, Christiane and Yang, Qiong and Adams, Hieab H H and Amouyel, Philippe and Beiser, Alexa and Buckley, Brendan M and Callisaya, Michele and Chauhan, Ganesh and de Craen, Anton J M and Dufouil, Carole and van Duijn, Cornelia M and Ford, Ian and Freudenberger, Paul and Gottesman, Rebecca F and Gudnason, Vilmundur and Heiss, Gerardo and Hofman, Albert and Lumley, Thomas and Martinez, Oliver and Mazoyer, Bernard and Moran, Chris and Niessen, Wiro J and Phan, Thanh and Psaty, Bruce M and Satizabal, Claudia L and Sattar, Naveed and Schilling, Sabrina and Shibata, Dean K and Slagboom, P Eline and Smith, Albert and Stott, David J and Taylor, Kent D and Thomson, Russell and T{\"o}glhofer, Anna M and Tzourio, Christophe and van Buchem, Mark and Wang, Jing and Westendorp, Rudi G J and Windham, B Gwen and Vernooij, Meike W and Zijdenbos, Alex and Beare, Richard and Debette, Stephanie and Ikram, M Arfan and Jukema, J Wouter and Launer, Lenore J and Longstreth, W T and Mosley, Thomas H and Seshadri, Sudha and Schmidt, Helena and Schmidt, Reinhold} } @article {7587, title = {Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer{\textquoteright}s disease.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Sep}, pages = {1373-1384}, abstract = {

We identified rare coding variants associated with Alzheimer{\textquoteright}s disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 {\texttimes} 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 {\texttimes} 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer{\textquoteright}s disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 {\texttimes} 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 {\texttimes} 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 {\texttimes} 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer{\textquoteright}s disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer{\textquoteright}s disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer{\textquoteright}s disease.

}, keywords = {Adaptor Proteins, Signal Transducing, Alzheimer Disease, Amino Acid Sequence, Case-Control Studies, Exome, Gene Expression Profiling, Gene Frequency, Genetic Predisposition to Disease, Genotype, Humans, Immunity, Innate, Linkage Disequilibrium, Membrane Glycoproteins, Microglia, Odds Ratio, Phospholipase C gamma, Polymorphism, Single Nucleotide, Protein Interaction Maps, Receptors, Immunologic, Sequence Homology, Amino Acid}, issn = {1546-1718}, doi = {10.1038/ng.3916}, author = {Sims, Rebecca and van der Lee, Sven J and Naj, Adam C and Bellenguez, C{\'e}line and Badarinarayan, Nandini and Jakobsdottir, Johanna and Kunkle, Brian W and Boland, Anne and Raybould, Rachel and Bis, Joshua C and Martin, Eden R and Grenier-Boley, Benjamin and Heilmann-Heimbach, Stefanie and Chouraki, Vincent and Kuzma, Amanda B and Sleegers, Kristel and Vronskaya, Maria and Ruiz, Agustin and Graham, Robert R and Olaso, Robert and Hoffmann, Per and Grove, Megan L and Vardarajan, Badri N and Hiltunen, Mikko and N{\"o}then, Markus M and White, Charles C and Hamilton-Nelson, Kara L and Epelbaum, Jacques and Maier, Wolfgang and Choi, Seung-Hoan and Beecham, Gary W and Dulary, C{\'e}cile and Herms, Stefan and Smith, Albert V and Funk, Cory C and Derbois, C{\'e}line and Forstner, Andreas J and Ahmad, Shahzad and Li, Hongdong and Bacq, Delphine and Harold, Denise and Satizabal, Claudia L and Valladares, Otto and Squassina, Alessio and Thomas, Rhodri and Brody, Jennifer A and Qu, Liming and S{\'a}nchez-Juan, Pascual and Morgan, Taniesha and Wolters, Frank J and Zhao, Yi and Garcia, Florentino Sanchez and Denning, Nicola and Fornage, Myriam and Malamon, John and Naranjo, Maria Candida Deniz and Majounie, Elisa and Mosley, Thomas H and Dombroski, Beth and Wallon, David and Lupton, Michelle K and Dupuis, Jos{\'e}e and Whitehead, Patrice and Fratiglioni, Laura and Medway, Christopher and Jian, Xueqiu and Mukherjee, Shubhabrata and Keller, Lina and Brown, Kristelle and Lin, Honghuang and Cantwell, Laura B and Panza, Francesco and McGuinness, Bernadette and Moreno-Grau, Sonia and Burgess, Jeremy D and Solfrizzi, Vincenzo and Proitsi, Petra and Adams, Hieab H and Allen, Mariet and Seripa, Davide and Pastor, Pau and Cupples, L Adrienne and Price, Nathan D and Hannequin, Didier and Frank-Garc{\'\i}a, Ana and Levy, Daniel and Chakrabarty, Paramita and Caffarra, Paolo and Giegling, Ina and Beiser, Alexa S and Giedraitis, Vilmantas and Hampel, Harald and Garcia, Melissa E and Wang, Xue and Lannfelt, Lars and Mecocci, Patrizia and Eiriksdottir, Gudny and Crane, Paul K and Pasquier, Florence and Boccardi, Virginia and Hen{\'a}ndez, Isabel and Barber, Robert C and Scherer, Martin and Tarraga, Lluis and Adams, Perrie M and Leber, Markus and Chen, Yuning and Albert, Marilyn S and Riedel-Heller, Steffi and Emilsson, Valur and Beekly, Duane and Braae, Anne and Schmidt, Reinhold and Blacker, Deborah and Masullo, Carlo and Schmidt, Helena and Doody, Rachelle S and Spalletta, Gianfranco and Jr, W T Longstreth and Fairchild, Thomas J and Boss{\`u}, Paola and Lopez, Oscar L and Frosch, Matthew P and Sacchinelli, Eleonora and Ghetti, Bernardino and Yang, Qiong and Huebinger, Ryan M and Jessen, Frank and Li, Shuo and Kamboh, M Ilyas and Morris, John and Sotolongo-Grau, Oscar and Katz, Mindy J and Corcoran, Chris and Dunstan, Melanie and Braddel, Amy and Thomas, Charlene and Meggy, Alun and Marshall, Rachel and Gerrish, Amy and Chapman, Jade and Aguilar, Miquel and Taylor, Sarah and Hill, Matt and Fair{\'e}n, M{\`o}nica D{\'\i}ez and Hodges, Angela and Vellas, Bruno and Soininen, Hilkka and Kloszewska, Iwona and Daniilidou, Makrina and Uphill, James and Patel, Yogen and Hughes, Joseph T and Lord, Jenny and Turton, James and Hartmann, Annette M and Cecchetti, Roberta and Fenoglio, Chiara and Serpente, Maria and Arcaro, Marina and Caltagirone, Carlo and Orfei, Maria Donata and Ciaramella, Antonio and Pichler, Sabrina and Mayhaus, Manuel and Gu, Wei and Lleo, Alberto and Fortea, Juan and Blesa, Rafael and Barber, Imelda S and Brookes, Keeley and Cupidi, Chiara and Maletta, Raffaele Giovanni and Carrell, David and Sorbi, Sandro and Moebus, Susanne and Urbano, Maria and Pilotto, Alberto and Kornhuber, Johannes and Bosco, Paolo and Todd, Stephen and Craig, David and Johnston, Janet and Gill, Michael and Lawlor, Brian and Lynch, Aoibhinn and Fox, Nick C and Hardy, John and Albin, Roger L and Apostolova, Liana G and Arnold, Steven E and Asthana, Sanjay and Atwood, Craig S and Baldwin, Clinton T and Barnes, Lisa L and Barral, Sandra and Beach, Thomas G and Becker, James T and Bigio, Eileen H and Bird, Thomas D and Boeve, Bradley F and Bowen, James D and Boxer, Adam and Burke, James R and Burns, Jeffrey M and Buxbaum, Joseph D and Cairns, Nigel J and Cao, Chuanhai and Carlson, Chris S and Carlsson, Cynthia M and Carney, Regina M and Carrasquillo, Minerva M and Carroll, Steven L and Diaz, Carolina Ceballos and Chui, Helena C and Clark, David G and Cribbs, David H and Crocco, Elizabeth A and DeCarli, Charles and Dick, Malcolm and Duara, Ranjan and Evans, Denis A and Faber, Kelley M and Fallon, Kenneth B and Fardo, David W and Farlow, Martin R and Ferris, Steven and Foroud, Tatiana M and Galasko, Douglas R and Gearing, Marla and Geschwind, Daniel H and Gilbert, John R and Graff-Radford, Neill R and Green, Robert C and Growdon, John H and Hamilton, Ronald L and Harrell, Lindy E and Honig, Lawrence S and Huentelman, Matthew J and Hulette, Christine M and Hyman, Bradley T and Jarvik, Gail P and Abner, Erin and Jin, Lee-Way and Jun, Gyungah and Karydas, Anna and Kaye, Jeffrey A and Kim, Ronald and Kowall, Neil W and Kramer, Joel H and LaFerla, Frank M and Lah, James J and Leverenz, James B and Levey, Allan I and Li, Ge and Lieberman, Andrew P and Lunetta, Kathryn L and Lyketsos, Constantine G and Marson, Daniel C and Martiniuk, Frank and Mash, Deborah C and Masliah, Eliezer and McCormick, Wayne C and McCurry, Susan M and McDavid, Andrew N and McKee, Ann C and Mesulam, Marsel and Miller, Bruce L and Miller, Carol A and Miller, Joshua W and Morris, John C and Murrell, Jill R and Myers, Amanda J and O{\textquoteright}Bryant, Sid and Olichney, John M and Pankratz, Vernon S and Parisi, Joseph E and Paulson, Henry L and Perry, William and Peskind, Elaine and Pierce, Aimee and Poon, Wayne W and Potter, Huntington and Quinn, Joseph F and Raj, Ashok and Raskind, Murray and Reisberg, Barry and Reitz, Christiane and Ringman, John M and Roberson, Erik D and Rogaeva, Ekaterina and Rosen, Howard J and Rosenberg, Roger N and Sager, Mark A and Saykin, Andrew J and Schneider, Julie A and Schneider, Lon S and Seeley, William W and Smith, Amanda G and Sonnen, Joshua A and Spina, Salvatore and Stern, Robert A and Swerdlow, Russell H and Tanzi, Rudolph E and Thornton-Wells, Tricia A and Trojanowski, John Q and Troncoso, Juan C and Van Deerlin, Vivianna M and Van Eldik, Linda J and Vinters, Harry V and Vonsattel, Jean Paul and Weintraub, Sandra and Welsh-Bohmer, Kathleen A and Wilhelmsen, Kirk C and Williamson, Jennifer and Wingo, Thomas S and Woltjer, Randall L and Wright, Clinton B and Yu, Chang-En and Yu, Lei and Garzia, Fabienne and Golamaully, Feroze and Septier, Gislain and Engelborghs, Sebastien and Vandenberghe, Rik and De Deyn, Peter P and Fernadez, Carmen Mu{\~n}oz and Benito, Yoland Aladro and Thonberg, H{\r a}kan and Forsell, Charlotte and Lilius, Lena and Kinhult-St{\r a}hlbom, Anne and Kilander, Lena and Brundin, RoseMarie and Concari, Letizia and Helisalmi, Seppo and Koivisto, Anne Maria and Haapasalo, Annakaisa and Dermecourt, Vincent and Fi{\'e}vet, Nathalie and Hanon, Olivier and Dufouil, Carole and Brice, Alexis and Ritchie, Karen and Dubois, Bruno and Himali, Jayanadra J and Keene, C Dirk and Tschanz, JoAnn and Fitzpatrick, Annette L and Kukull, Walter A and Norton, Maria and Aspelund, Thor and Larson, Eric B and Munger, Ron and Rotter, Jerome I and Lipton, Richard B and Bullido, Mar{\'\i}a J and Hofman, Albert and Montine, Thomas J and Coto, Eliecer and Boerwinkle, Eric and Petersen, Ronald C and Alvarez, Victoria and Rivadeneira, Fernando and Reiman, Eric M and Gallo, Maura and O{\textquoteright}Donnell, Christopher J and Reisch, Joan S and Bruni, Amalia Cecilia and Royall, Donald R and Dichgans, Martin and Sano, Mary and Galimberti, Daniela and St George-Hyslop, Peter and Scarpini, Elio and Tsuang, Debby W and Mancuso, Michelangelo and Bonuccelli, Ubaldo and Winslow, Ashley R and Daniele, Antonio and Wu, Chuang-Kuo and Peters, Oliver and Nacmias, Benedetta and Riemenschneider, Matthias and Heun, Reinhard and Brayne, Carol and Rubinsztein, David C and Bras, Jose and Guerreiro, Rita and Al-Chalabi, Ammar and Shaw, Christopher E and Collinge, John and Mann, David and Tsolaki, Magda and Clarimon, Jordi and Sussams, Rebecca and Lovestone, Simon and O{\textquoteright}Donovan, Michael C and Owen, Michael J and Behrens, Timothy W and Mead, Simon and Goate, Alison M and Uitterlinden, Andr{\'e} G and Holmes, Clive and Cruchaga, Carlos and Ingelsson, Martin and Bennett, David A and Powell, John and Golde, Todd E and Graff, Caroline and De Jager, Philip L and Morgan, Kevin and Ertekin-Taner, Nilufer and Combarros, Onofre and Psaty, Bruce M and Passmore, Peter and Younkin, Steven G and Berr, Claudine and Gudnason, Vilmundur and Rujescu, Dan and Dickson, Dennis W and Dartigues, Jean-Fran{\c c}ois and DeStefano, Anita L and Ortega-Cubero, Sara and Hakonarson, Hakon and Campion, Dominique and Boada, Merce and Kauwe, John Keoni and Farrer, Lindsay A and Van Broeckhoven, Christine and Ikram, M Arfan and Jones, Lesley and Haines, Jonathan L and Tzourio, Christophe and Launer, Lenore J and Escott-Price, Valentina and Mayeux, Richard and Deleuze, Jean-Francois and Amin, Najaf and Holmans, Peter A and Pericak-Vance, Margaret A and Amouyel, Philippe and van Duijn, Cornelia M and Ramirez, Alfredo and Wang, Li-San and Lambert, Jean-Charles and Seshadri, Sudha and Williams, Julie and Schellenberg, Gerard D} } @article {7849, title = {Genome-wide association study of 23,500 individuals identifies 7 loci associated with brain ventricular volume.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 Sep 26}, pages = {3945}, abstract = {

The volume of the lateral ventricles (LV) increases with age and their abnormal enlargement is a key feature of several neurological and psychiatric diseases. Although lateral ventricular volume is heritable, a comprehensive investigation of its genetic determinants is lacking. In this meta-analysis of genome-wide association studies of 23,533 healthy middle-aged to elderly individuals from 26 population-based cohorts, we identify 7 genetic loci associated with LV volume. These loci map to chromosomes 3q28, 7p22.3, 10p12.31, 11q23.1, 12q23.3, 16q24.2, and 22q13.1 and implicate pathways related to tau pathology, S1P signaling, and cytoskeleton organization. We also report a significant genetic overlap between the thalamus and LV volumes (ρ = -0.59, p-value = 3.14 {\texttimes} 10), suggesting that these brain structures may share a common biology. These genetic associations of LV volume provide insights into brain morphology.

}, issn = {2041-1723}, doi = {10.1038/s41467-018-06234-w}, author = {Vojinovic, Dina and Adams, Hieab H and Jian, Xueqiu and Yang, Qiong and Smith, Albert Vernon and Bis, Joshua C and Teumer, Alexander and Scholz, Markus and Armstrong, Nicola J and Hofer, Edith and Saba, Yasaman and Luciano, Michelle and Bernard, Manon and Trompet, Stella and Yang, Jingyun and Gillespie, Nathan A and van der Lee, Sven J and Neumann, Alexander and Ahmad, Shahzad and Andreassen, Ole A and Ames, David and Amin, Najaf and Arfanakis, Konstantinos and Bastin, Mark E and Becker, Diane M and Beiser, Alexa S and Beyer, Frauke and Brodaty, Henry and Bryan, R Nick and B{\"u}low, Robin and Dale, Anders M and De Jager, Philip L and Deary, Ian J and DeCarli, Charles and Fleischman, Debra A and Gottesman, Rebecca F and van der Grond, Jeroen and Gudnason, Vilmundur and Harris, Tamara B and Homuth, Georg and Knopman, David S and Kwok, John B and Lewis, Cora E and Li, Shuo and Loeffler, Markus and Lopez, Oscar L and Maillard, Pauline and El Marroun, Hanan and Mather, Karen A and Mosley, Thomas H and Muetzel, Ryan L and Nauck, Matthias and Nyquist, Paul A and Panizzon, Matthew S and Pausova, Zdenka and Psaty, Bruce M and Rice, Ken and Rotter, Jerome I and Royle, Natalie and Satizabal, Claudia L and Schmidt, Reinhold and Schofield, Peter R and Schreiner, Pamela J and Sidney, Stephen and Stott, David J and Thalamuthu, Anbupalam and Uitterlinden, Andr{\'e} G and Vald{\'e}s Hern{\'a}ndez, Maria C and Vernooij, Meike W and Wen, Wei and White, Tonya and Witte, A Veronica and Wittfeld, Katharina and Wright, Margaret J and Yanek, Lisa R and Tiemeier, Henning and Kremen, William S and Bennett, David A and Jukema, J Wouter and Paus, Tom{\'a}{\v s} and Wardlaw, Joanna M and Schmidt, Helena and Sachdev, Perminder S and Villringer, Arno and Grabe, Hans J{\"o}rgen and Longstreth, W T and van Duijn, Cornelia M and Launer, Lenore J and Seshadri, Sudha and Ikram, M Arfan and Fornage, Myriam} } @article {8206, title = {Genetic architecture of subcortical brain structures in 38,851 individuals.}, journal = {Nat Genet}, volume = {51}, year = {2019}, month = {2019 Nov}, pages = {1624-1636}, abstract = {

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

}, issn = {1546-1718}, doi = {10.1038/s41588-019-0511-y}, author = {Satizabal, Claudia L and Adams, Hieab H H and Hibar, Derrek P and White, Charles C and Knol, Maria J and Stein, Jason L and Scholz, Markus and Sargurupremraj, Muralidharan and Jahanshad, Neda and Roshchupkin, Gennady V and Smith, Albert V and Bis, Joshua C and Jian, Xueqiu and Luciano, Michelle and Hofer, Edith and Teumer, Alexander and van der Lee, Sven J and Yang, Jingyun and Yanek, Lisa R and Lee, Tom V and Li, Shuo and Hu, Yanhui and Koh, Jia Yu and Eicher, John D and Desrivi{\`e}res, Sylvane and Arias-Vasquez, Alejandro and Chauhan, Ganesh and Athanasiu, Lavinia and Renter{\'\i}a, Miguel E and Kim, Sungeun and Hoehn, David and Armstrong, Nicola J and Chen, Qiang and Holmes, Avram J and den Braber, Anouk and Kloszewska, Iwona and Andersson, Micael and Espeseth, Thomas and Grimm, Oliver and Abramovic, Lucija and Alhusaini, Saud and Milaneschi, Yuri and Papmeyer, Martina and Axelsson, Tomas and Ehrlich, Stefan and Roiz-Santia{\~n}ez, Roberto and Kraemer, Bernd and H{\r a}berg, Asta K and Jones, Hannah J and Pike, G Bruce and Stein, Dan J and Stevens, Allison and Bralten, Janita and Vernooij, Meike W and Harris, Tamara B and Filippi, Irina and Witte, A Veronica and Guadalupe, Tulio and Wittfeld, Katharina and Mosley, Thomas H and Becker, James T and Doan, Nhat Trung and Hagenaars, Saskia P and Saba, Yasaman and Cuellar-Partida, Gabriel and Amin, Najaf and Hilal, Saima and Nho, Kwangsik and Mirza-Schreiber, Nazanin and Arfanakis, Konstantinos and Becker, Diane M and Ames, David and Goldman, Aaron L and Lee, Phil H and Boomsma, Dorret I and Lovestone, Simon and Giddaluru, Sudheer and Le Hellard, Stephanie and Mattheisen, Manuel and Bohlken, Marc M and Kasperaviciute, Dalia and Schmaal, Lianne and Lawrie, Stephen M and Agartz, Ingrid and Walton, Esther and Tordesillas-Gutierrez, Diana and Davies, Gareth E and Shin, Jean and Ipser, Jonathan C and Vinke, Louis N and Hoogman, Martine and Jia, Tianye and Burkhardt, Ralph and Klein, Marieke and Crivello, Fabrice and Janowitz, Deborah and Carmichael, Owen and Haukvik, Unn K and Aribisala, Benjamin S and Schmidt, Helena and Strike, Lachlan T and Cheng, Ching-Yu and Risacher, Shannon L and P{\"u}tz, Benno and Fleischman, Debra A and Assareh, Amelia A and Mattay, Venkata S and Buckner, Randy L and Mecocci, Patrizia and Dale, Anders M and Cichon, Sven and Boks, Marco P and Matarin, Mar and Penninx, Brenda W J H and Calhoun, Vince D and Chakravarty, M Mallar and Marquand, Andre F and Macare, Christine and Kharabian Masouleh, Shahrzad and Oosterlaan, Jaap and Amouyel, Philippe and Hegenscheid, Katrin and Rotter, Jerome I and Schork, Andrew J and Liewald, David C M and de Zubicaray, Greig I and Wong, Tien Yin and Shen, Li and S{\"a}mann, Philipp G and Brodaty, Henry and Roffman, Joshua L and de Geus, Eco J C and Tsolaki, Magda and Erk, Susanne and van Eijk, Kristel R and Cavalleri, Gianpiero L and van der Wee, Nic J A and McIntosh, Andrew M and Gollub, Randy L and Bulayeva, Kazima B and Bernard, Manon and Richards, Jennifer S and Himali, Jayandra J and Loeffler, Markus and Rommelse, Nanda and Hoffmann, Wolfgang and Westlye, Lars T and Vald{\'e}s Hern{\'a}ndez, Maria C and Hansell, Narelle K and van Erp, Theo G M and Wolf, Christiane and Kwok, John B J and Vellas, Bruno and Heinz, Andreas and Olde Loohuis, Loes M and Delanty, Norman and Ho, Beng-Choon and Ching, Christopher R K and Shumskaya, Elena and Singh, Baljeet and Hofman, Albert and van der Meer, Dennis and Homuth, Georg and Psaty, Bruce M and Bastin, Mark E and Montgomery, Grant W and Foroud, Tatiana M and Reppermund, Simone and Hottenga, Jouke-Jan and Simmons, Andrew and Meyer-Lindenberg, Andreas and Cahn, Wiepke and Whelan, Christopher D and van Donkelaar, Marjolein M J and Yang, Qiong and Hosten, Norbert and Green, Robert C and Thalamuthu, Anbupalam and Mohnke, Sebastian and Hulshoff Pol, Hilleke E and Lin, Honghuang and Jack, Clifford R and Schofield, Peter R and M{\"u}hleisen, Thomas W and Maillard, Pauline and Potkin, Steven G and Wen, Wei and Fletcher, Evan and Toga, Arthur W and Gruber, Oliver and Huentelman, Matthew and Davey Smith, George and Launer, Lenore J and Nyberg, Lars and J{\"o}nsson, Erik G and Crespo-Facorro, Benedicto and Koen, Nastassja and Greve, Douglas N and Uitterlinden, Andr{\'e} G and Weinberger, Daniel R and Steen, Vidar M and Fedko, Iryna O and Groenewold, Nynke A and Niessen, Wiro J and Toro, Roberto and Tzourio, Christophe and Longstreth, William T and Ikram, M Kamran and Smoller, Jordan W and van Tol, Marie-Jose and Sussmann, Jessika E and Paus, Tom{\'a}{\v s} and Lema{\^\i}tre, Herv{\'e} and Schroeter, Matthias L and Mazoyer, Bernard and Andreassen, Ole A and Holsboer, Florian and Depondt, Chantal and Veltman, Dick J and Turner, Jessica A and Pausova, Zdenka and Schumann, Gunter and van Rooij, Daan and Djurovic, Srdjan and Deary, Ian J and McMahon, Katie L and M{\"u}ller-Myhsok, Bertram and Brouwer, Rachel M and Soininen, Hilkka and Pandolfo, Massimo and Wassink, Thomas H and Cheung, Joshua W and Wolfers, Thomas and Martinot, Jean-Luc and Zwiers, Marcel P and Nauck, Matthias and Melle, Ingrid and Martin, Nicholas G and Kanai, Ryota and Westman, Eric and Kahn, Ren{\'e} S and Sisodiya, Sanjay M and White, Tonya and Saremi, Arvin and van Bokhoven, Hans and Brunner, Han G and V{\"o}lzke, Henry and Wright, Margaret J and van {\textquoteright}t Ent, Dennis and N{\"o}then, Markus M and Ophoff, Roel A and Buitelaar, Jan K and Fern{\'a}ndez, Guill{\'e}n and Sachdev, Perminder S and Rietschel, Marcella and van Haren, Neeltje E M and Fisher, Simon E and Beiser, Alexa S and Francks, Clyde and Saykin, Andrew J and Mather, Karen A and Romanczuk-Seiferth, Nina and Hartman, Catharina A and DeStefano, Anita L and Heslenfeld, Dirk J and Weiner, Michael W and Walter, Henrik and Hoekstra, Pieter J and Nyquist, Paul A and Franke, Barbara and Bennett, David A and Grabe, Hans J and Johnson, Andrew D and Chen, Christopher and van Duijn, Cornelia M and Lopez, Oscar L and Fornage, Myriam and Wardlaw, Joanna M and Schmidt, Reinhold and DeCarli, Charles and De Jager, Philip L and Villringer, Arno and Debette, Stephanie and Gudnason, Vilmundur and Medland, Sarah E and Shulman, Joshua M and Thompson, Paul M and Seshadri, Sudha and Ikram, M Arfan} } @article {7977, title = {Genetic meta-analysis of diagnosed Alzheimer{\textquoteright}s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.}, journal = {Nat Genet}, volume = {51}, year = {2019}, month = {2019 Mar}, pages = {414-430}, abstract = {

Risk for late-onset Alzheimer{\textquoteright}s disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer{\textquoteright}s or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer{\textquoteright}s disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 {\texttimes} 10), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

}, issn = {1546-1718}, doi = {10.1038/s41588-019-0358-2}, author = {Kunkle, Brian W and Grenier-Boley, Benjamin and Sims, Rebecca and Bis, Joshua C and Damotte, Vincent and Naj, Adam C and Boland, Anne and Vronskaya, Maria and van der Lee, Sven J and Amlie-Wolf, Alexandre and Bellenguez, C{\'e}line and Frizatti, Aura and Chouraki, Vincent and Martin, Eden R and Sleegers, Kristel and Badarinarayan, Nandini and Jakobsdottir, Johanna and Hamilton-Nelson, Kara L and Moreno-Grau, Sonia and Olaso, Robert and Raybould, Rachel and Chen, Yuning and Kuzma, Amanda B and Hiltunen, Mikko and Morgan, Taniesha and Ahmad, Shahzad and Vardarajan, Badri N and Epelbaum, Jacques and Hoffmann, Per and Boada, Merce and Beecham, Gary W and Garnier, Jean-Guillaume and Harold, Denise and Fitzpatrick, Annette L and Valladares, Otto and Moutet, Marie-Laure and Gerrish, Amy and Smith, Albert V and Qu, Liming and Bacq, Delphine and Denning, Nicola and Jian, Xueqiu and Zhao, Yi and Del Zompo, Maria and Fox, Nick C and Choi, Seung-Hoan and Mateo, Ignacio and Hughes, Joseph T and Adams, Hieab H and Malamon, John and Sanchez-Garcia, Florentino and Patel, Yogen and Brody, Jennifer A and Dombroski, Beth A and Naranjo, Maria Candida Deniz and Daniilidou, Makrina and Eiriksdottir, Gudny and Mukherjee, Shubhabrata and Wallon, David and Uphill, James and Aspelund, Thor and Cantwell, Laura B and Garzia, Fabienne and Galimberti, Daniela and Hofer, Edith and Butkiewicz, Mariusz and Fin, Bertrand and Scarpini, Elio and Sarnowski, Chloe and Bush, Will S and Meslage, St{\'e}phane and Kornhuber, Johannes and White, Charles C and Song, Yuenjoo and Barber, Robert C and Engelborghs, Sebastiaan and Sordon, Sabrina and Voijnovic, Dina and Adams, Perrie M and Vandenberghe, Rik and Mayhaus, Manuel and Cupples, L Adrienne and Albert, Marilyn S and De Deyn, Peter P and Gu, Wei and Himali, Jayanadra J and Beekly, Duane and Squassina, Alessio and Hartmann, Annette M and Orellana, Adelina and Blacker, Deborah and Rodriguez-Rodriguez, Eloy and Lovestone, Simon and Garcia, Melissa E and Doody, Rachelle S and Munoz-Fernadez, Carmen and Sussams, Rebecca and Lin, Honghuang and Fairchild, Thomas J and Benito, Yolanda A and Holmes, Clive and Karamuji{\'c}-{\v C}omi{\'c}, Hata and Frosch, Matthew P and Thonberg, H{\r a}kan and Maier, Wolfgang and Roschupkin, Gena and Ghetti, Bernardino and Giedraitis, Vilmantas and Kawalia, Amit and Li, Shuo and Huebinger, Ryan M and Kilander, Lena and Moebus, Susanne and Hernandez, Isabel and Kamboh, M Ilyas and Brundin, RoseMarie and Turton, James and Yang, Qiong and Katz, Mindy J and Concari, Letizia and Lord, Jenny and Beiser, Alexa S and Keene, C Dirk and Helisalmi, Seppo and Kloszewska, Iwona and Kukull, Walter A and Koivisto, Anne Maria and Lynch, Aoibhinn and Tarraga, Lluis and Larson, Eric B and Haapasalo, Annakaisa and Lawlor, Brian and Mosley, Thomas H and Lipton, Richard B and Solfrizzi, Vincenzo and Gill, Michael and Longstreth, W T and Montine, Thomas J and Frisardi, Vincenza and Diez-Fairen, Monica and Rivadeneira, Fernando and Petersen, Ronald C and Deramecourt, Vincent and Alvarez, Ignacio and Salani, Francesca and Ciaramella, Antonio and Boerwinkle, Eric and Reiman, Eric M and Fi{\'e}vet, Nathalie and Rotter, Jerome I and Reisch, Joan S and Hanon, Olivier and Cupidi, Chiara and Andre Uitterlinden, A G and Royall, Donald R and Dufouil, Carole and Maletta, Raffaele Giovanni and de Rojas, Itziar and Sano, Mary and Brice, Alexis and Cecchetti, Roberta and George-Hyslop, Peter St and Ritchie, Karen and Tsolaki, Magda and Tsuang, Debby W and Dubois, Bruno and Craig, David and Wu, Chuang-Kuo and Soininen, Hilkka and Avramidou, Despoina and Albin, Roger L and Fratiglioni, Laura and Germanou, Antonia and Apostolova, Liana G and Keller, Lina and Koutroumani, Maria and Arnold, Steven E and Panza, Francesco and Gkatzima, Olymbia and Asthana, Sanjay and Hannequin, Didier and Whitehead, Patrice and Atwood, Craig S and Caffarra, Paolo and Hampel, Harald and Quintela, In{\'e}s and Carracedo, Angel and Lannfelt, Lars and Rubinsztein, David C and Barnes, Lisa L and Pasquier, Florence and Fr{\"o}lich, Lutz and Barral, Sandra and McGuinness, Bernadette and Beach, Thomas G and Johnston, Janet A and Becker, James T and Passmore, Peter and Bigio, Eileen H and Schott, Jonathan M and Bird, Thomas D and Warren, Jason D and Boeve, Bradley F and Lupton, Michelle K and Bowen, James D and Proitsi, Petra and Boxer, Adam and Powell, John F and Burke, James R and Kauwe, John S K and Burns, Jeffrey M and Mancuso, Michelangelo and Buxbaum, Joseph D and Bonuccelli, Ubaldo and Cairns, Nigel J and McQuillin, Andrew and Cao, Chuanhai and Livingston, Gill and Carlson, Chris S and Bass, Nicholas J and Carlsson, Cynthia M and Hardy, John and Carney, Regina M and Bras, Jose and Carrasquillo, Minerva M and Guerreiro, Rita and Allen, Mariet and Chui, Helena C and Fisher, Elizabeth and Masullo, Carlo and Crocco, Elizabeth A and DeCarli, Charles and Bisceglio, Gina and Dick, Malcolm and Ma, Li and Duara, Ranjan and Graff-Radford, Neill R and Evans, Denis A and Hodges, Angela and Faber, Kelley M and Scherer, Martin and Fallon, Kenneth B and Riemenschneider, Matthias and Fardo, David W and Heun, Reinhard and Farlow, Martin R and K{\"o}lsch, Heike and Ferris, Steven and Leber, Markus and Foroud, Tatiana M and Heuser, Isabella and Galasko, Douglas R and Giegling, Ina and Gearing, Marla and H{\"u}ll, Michael and Geschwind, Daniel H and Gilbert, John R and Morris, John and Green, Robert C and Mayo, Kevin and Growdon, John H and Feulner, Thomas and Hamilton, Ronald L and Harrell, Lindy E and Drichel, Dmitriy and Honig, Lawrence S and Cushion, Thomas D and Huentelman, Matthew J and Hollingworth, Paul and Hulette, Christine M and Hyman, Bradley T and Marshall, Rachel and Jarvik, Gail P and Meggy, Alun and Abner, Erin and Menzies, Georgina E and Jin, Lee-Way and Leonenko, Ganna and Real, Luis M and Jun, Gyungah R and Baldwin, Clinton T and Grozeva, Detelina and Karydas, Anna and Russo, Giancarlo and Kaye, Jeffrey A and Kim, Ronald and Jessen, Frank and Kowall, Neil W and Vellas, Bruno and Kramer, Joel H and Vardy, Emma and LaFerla, Frank M and J{\"o}ckel, Karl-Heinz and Lah, James J and Dichgans, Martin and Leverenz, James B and Mann, David and Levey, Allan I and Pickering-Brown, Stuart and Lieberman, Andrew P and Klopp, Norman and Lunetta, Kathryn L and Wichmann, H-Erich and Lyketsos, Constantine G and Morgan, Kevin and Marson, Daniel C and Brown, Kristelle and Martiniuk, Frank and Medway, Christopher and Mash, Deborah C and N{\"o}then, Markus M and Masliah, Eliezer and Hooper, Nigel M and McCormick, Wayne C and Daniele, Antonio and McCurry, Susan M and Bayer, Anthony and McDavid, Andrew N and Gallacher, John and McKee, Ann C and van den Bussche, Hendrik and Mesulam, Marsel and Brayne, Carol and Miller, Bruce L and Riedel-Heller, Steffi and Miller, Carol A and Miller, Joshua W and Al-Chalabi, Ammar and Morris, John C and Shaw, Christopher E and Myers, Amanda J and Wiltfang, Jens and O{\textquoteright}Bryant, Sid and Olichney, John M and Alvarez, Victoria and Parisi, Joseph E and Singleton, Andrew B and Paulson, Henry L and Collinge, John and Perry, William R and Mead, Simon and Peskind, Elaine and Cribbs, David H and Rossor, Martin and Pierce, Aimee and Ryan, Natalie S and Poon, Wayne W and Nacmias, Benedetta and Potter, Huntington and Sorbi, Sandro and Quinn, Joseph F and Sacchinelli, Eleonora and Raj, Ashok and Spalletta, Gianfranco and Raskind, Murray and Caltagirone, Carlo and Boss{\`u}, Paola and Orfei, Maria Donata and Reisberg, Barry and Clarke, Robert and Reitz, Christiane and Smith, A David and Ringman, John M and Warden, Donald and Roberson, Erik D and Wilcock, Gordon and Rogaeva, Ekaterina and Bruni, Amalia Cecilia and Rosen, Howard J and Gallo, Maura and Rosenberg, Roger N and Ben-Shlomo, Yoav and Sager, Mark A and Mecocci, Patrizia and Saykin, Andrew J and Pastor, Pau and Cuccaro, Michael L and Vance, Jeffery M and Schneider, Julie A and Schneider, Lori S and Slifer, Susan and Seeley, William W and Smith, Amanda G and Sonnen, Joshua A and Spina, Salvatore and Stern, Robert A and Swerdlow, Russell H and Tang, Mitchell and Tanzi, Rudolph E and Trojanowski, John Q and Troncoso, Juan C and Van Deerlin, Vivianna M and Van Eldik, Linda J and Vinters, Harry V and Vonsattel, Jean Paul and Weintraub, Sandra and Welsh-Bohmer, Kathleen A and Wilhelmsen, Kirk C and Williamson, Jennifer and Wingo, Thomas S and Woltjer, Randall L and Wright, Clinton B and Yu, Chang-En and Yu, Lei and Saba, Yasaman and Pilotto, Alberto and Bullido, Mar{\'\i}a J and Peters, Oliver and Crane, Paul K and Bennett, David and Bosco, Paola and Coto, Eliecer and Boccardi, Virginia and De Jager, Phil L and Lleo, Alberto and Warner, Nick and Lopez, Oscar L and Ingelsson, Martin and Deloukas, Panagiotis and Cruchaga, Carlos and Graff, Caroline and Gwilliam, Rhian and Fornage, Myriam and Goate, Alison M and S{\'a}nchez-Juan, Pascual and Kehoe, Patrick G and Amin, Najaf and Ertekin-Taner, Nilifur and Berr, Claudine and Debette, Stephanie and Love, Seth and Launer, Lenore J and Younkin, Steven G and Dartigues, Jean-Fran{\c c}ois and Corcoran, Chris and Ikram, M Arfan and Dickson, Dennis W and Nicolas, Ga{\"e}l and Campion, Dominique and Tschanz, JoAnn and Schmidt, Helena and Hakonarson, Hakon and Clarimon, Jordi and Munger, Ron and Schmidt, Reinhold and Farrer, Lindsay A and Van Broeckhoven, Christine and C O{\textquoteright}Donovan, Michael and DeStefano, Anita L and Jones, Lesley and Haines, Jonathan L and Deleuze, Jean-Francois and Owen, Michael J and Gudnason, Vilmundur and Mayeux, Richard and Escott-Price, Valentina and Psaty, Bruce M and Ramirez, Alfredo and Wang, Li-San and Ruiz, Agustin and van Duijn, Cornelia M and Holmans, Peter A and Seshadri, Sudha and Williams, Julie and Amouyel, Phillippe and Schellenberg, Gerard D and Lambert, Jean-Charles and Pericak-Vance, Margaret A} } @article {8287, title = {Association of CD14 with incident dementia and markers of brain aging and injury.}, journal = {Neurology}, volume = {94}, year = {2020}, month = {2020 01 21}, pages = {e254-e266}, abstract = {

OBJECTIVE: To test the hypothesis that the inflammatory marker plasma soluble CD14 (sCD14) associates with incident dementia and related endophenotypes in 2 community-based cohorts.

METHODS: Our samples included the prospective community-based Framingham Heart Study (FHS) and Cardiovascular Health Study (CHS) cohorts. Plasma sCD14 was measured at baseline and related to the incidence of dementia, domains of cognitive function, and MRI-defined brain volumes. Follow-up for dementia occurred over a mean of 10 years (SD 4) in the FHS and a mean of 6 years (SD 3) in the CHS.

RESULTS: We studied 1,588 participants from the FHS (mean age 69 {\textpm} 6 years, 47\% male, 131 incident events) and 3,129 participants from the CHS (mean age 72 {\textpm} 5 years, 41\% male, 724 incident events) for the risk of incident dementia. Meta-analysis across the 2 cohorts showed that each SD unit increase in sCD14 was associated with a 12\% increase in the risk of incident dementia (95\% confidence interval 1.03-1.23; = 0.01) following adjustments for age, sex, ε4 status, and vascular risk factors. Higher levels of sCD14 were associated with various cognitive and MRI markers of accelerated brain aging in both cohorts and with a greater progression of brain atrophy and a decline in executive function in the FHS.

CONCLUSION: sCD14 is an inflammatory marker related to brain atrophy, cognitive decline, and incident dementia.

}, issn = {1526-632X}, doi = {10.1212/WNL.0000000000008682}, author = {Pase, Matthew P and Himali, Jayandra J and Beiser, Alexa S and DeCarli, Charles and McGrath, Emer R and Satizabal, Claudia L and Aparicio, Hugo J and Adams, Hieab H H and Reiner, Alexander P and Longstreth, W T and Fornage, Myriam and Tracy, Russell P and Lopez, Oscar and Psaty, Bruce M and Levy, Daniel and Seshadri, Sudha and Bis, Joshua C} } @article {8506, title = {The genetic architecture of the human cerebral cortex}, journal = {Science}, volume = {367}, year = {2020}, month = {Aug-03-2021}, pages = {eaay6690}, issn = {0036-8075}, doi = {10.1126/science.aay6690}, url = {https://www.sciencemag.org/lookup/doi/10.1126/science.aay6690https://syndication.highwire.org/content/doi/10.1126/science.aay6690https://syndication.highwire.org/content/doi/10.1126/science.aay6690}, author = {Grasby, Katrina L. and Jahanshad, Neda and Painter, Jodie N. and Colodro-Conde, Luc{\'\i}a and Bralten, Janita and Hibar, Derrek P. and Lind, Penelope A. and Pizzagalli, Fabrizio and Ching, Christopher R. K. and McMahon, Mary Agnes B. and Shatokhina, Natalia and Zsembik, Leo C. P. and Thomopoulos, Sophia I. and Zhu, Alyssa H. and Strike, Lachlan T. and Agartz, Ingrid and Alhusaini, Saud and Almeida, Marcio A. A. and Aln{\ae}s, Dag and Amlien, Inge K. and Andersson, Micael and Ard, Tyler and Armstrong, Nicola J. and Ashley-Koch, Allison and Atkins, Joshua R. and Bernard, Manon and Brouwer, Rachel M. and Buimer, Elizabeth E. L. and B{\"u}low, Robin and B{\"u}rger, Christian and Cannon, Dara M. and Chakravarty, Mallar and Chen, Qiang and Cheung, Joshua W. and Couvy-Duchesne, Baptiste and Dale, Anders M. and Dalvie, Shareefa and de Araujo, T{\^a}nia K. and de Zubicaray, Greig I. and de Zwarte, Sonja M. C. and den Braber, Anouk and Doan, Nhat Trung and Dohm, Katharina and Ehrlich, Stefan and Engelbrecht, Hannah-Ruth and Erk, Susanne and Fan, Chun Chieh and Fedko, Iryna O. and Foley, Sonya F. and Ford, Judith M. and Fukunaga, Masaki and Garrett, Melanie E. and Ge, Tian and Giddaluru, Sudheer and Goldman, Aaron L. and Green, Melissa J. and Groenewold, Nynke A. and Grotegerd, Dominik and Gurholt, Tiril P. and Gutman, Boris A. and Hansell, Narelle K. and Harris, Mathew A. and Harrison, Marc B. and Haswell, Courtney C. and Hauser, Michael and Herms, Stefan and Heslenfeld, Dirk J. and Ho, New Fei and Hoehn, David and Hoffmann, Per and Holleran, Laurena and Hoogman, Martine and Hottenga, Jouke-Jan and Ikeda, Masashi and Janowitz, Deborah and Jansen, Iris E. and Jia, Tianye and Jockwitz, Christiane and Kanai, Ryota and Karama, Sherif and Kasperaviciute, Dalia and Kaufmann, Tobias and Kelly, Sinead and Kikuchi, Masataka and Klein, Marieke and Knapp, Michael and Knodt, Annchen R. and Kr{\"a}mer, Bernd and Lam, Max and Lancaster, Thomas M. and Lee, Phil H. and Lett, Tristram A. and Lewis, Lindsay B. and Lopes-Cendes, Iscia and Luciano, Michelle and Macciardi, Fabio and Marquand, Andre F. and Mathias, Samuel R. and Melzer, Tracy R. and Milaneschi, Yuri and Mirza-Schreiber, Nazanin and Moreira, Jose C. V. and M{\"u}hleisen, Thomas W. and M{\"u}ller-Myhsok, Bertram and Najt, Pablo and Nakahara, Soichiro and Nho, Kwangsik and Olde Loohuis, Loes M. and Orfanos, Dimitri Papadopoulos and Pearson, John F. and Pitcher, Toni L. and P{\"u}tz, Benno and Quid{\'e}, Yann and Ragothaman, Anjanibhargavi and Rashid, Faisal M. and Reay, William R. and Redlich, Ronny and Reinbold, C{\'e}line S. and Repple, Jonathan and Richard, Genevi{\`e}ve and Riedel, Brandalyn C. and Risacher, Shannon L. and Rocha, Cristiane S. and Mota, Nina Roth and Salminen, Lauren and Saremi, Arvin and Saykin, Andrew J. and Schlag, Fenja and Schmaal, Lianne and Schofield, Peter R. and Secolin, Rodrigo and Shapland, Chin Yang and Shen, Li and Shin, Jean and Shumskaya, Elena and S{\o}nderby, Ida E. and Sprooten, Emma and Tansey, Katherine E. and Teumer, Alexander and Thalamuthu, Anbupalam and Tordesillas-Gutierrez, Diana and Turner, Jessica A. and Uhlmann, Anne and Vallerga, Costanza Ludovica and van der Meer, Dennis and van Donkelaar, Marjolein M. J. and van Eijk, Liza and van Erp, Theo G. M. and van Haren, Neeltje E. M. and van Rooij, Daan and van Tol, Marie-Jose and Veldink, Jan H. and Verhoef, Ellen and Walton, Esther and Wang, Mingyuan and Wang, Yunpeng and Wardlaw, Joanna M. and Wen, Wei and Westlye, Lars T. and Whelan, Christopher D. and Witt, Stephanie H. and Wittfeld, Katharina and Wolf, Christiane and Wolfers, Thomas and Wu, Jing Qin and Yasuda, Clarissa L. and Zaremba, Dario and Zhang, Zuo and Zwiers, Marcel P. and Artiges, Eric and Assareh, Amelia A. and Ayesa-Arriola, Rosa and Belger, Aysenil and Brandt, Christine L. and Brown, Gregory G. and Cichon, Sven and Curran, Joanne E. and Davies, Gareth E. and Degenhardt, Franziska and Dennis, Michelle F. and Dietsche, Bruno and Djurovic, Srdjan and Doherty, Colin P. and Espiritu, Ryan and Garijo, Daniel and Gil, Yolanda and Gowland, Penny A. and Green, Robert C. and H{\"a}usler, Alexander N. and Heindel, Walter and Ho, Beng-Choon and Hoffmann, Wolfgang U. and Holsboer, Florian and Homuth, Georg and Hosten, Norbert and Jack, Clifford R. and Jang, MiHyun and Jansen, Andreas and Kimbrel, Nathan A. and Kolsk{\r a}r, Knut and Koops, Sanne and Krug, Axel and Lim, Kelvin O. and Luykx, Jurjen J. and Mathalon, Daniel H. and Mather, Karen A. and Mattay, Venkata S. and Matthews, Sarah and Mayoral Van Son, Jaqueline and McEwen, Sarah C. and Melle, Ingrid and Morris, Derek W. and Mueller, Bryon A. and Nauck, Matthias and Nordvik, Jan E. and N{\"o}then, Markus M. and O{\textquoteright}Leary, Daniel S. and Opel, Nils and Martinot, Marie-Laure Paill{\`e}re and Pike, G. Bruce and Preda, Adrian and Quinlan, Erin B. and Rasser, Paul E. and Ratnakar, Varun and Reppermund, Simone and Steen, Vidar M. and Tooney, Paul A. and Torres, F{\'a}bio R. and Veltman, Dick J. and Voyvodic, James T. and Whelan, Robert and White, Tonya and Yamamori, Hidenaga and Adams, Hieab H. H. and Bis, Joshua C. and Debette, Stephanie and DeCarli, Charles and Fornage, Myriam and Gudnason, Vilmundur and Hofer, Edith and Ikram, M. Arfan and Launer, Lenore and Longstreth, W. T. and Lopez, Oscar L. and Mazoyer, Bernard and Mosley, Thomas H. and Roshchupkin, Gennady V. and Satizabal, Claudia L. and Schmidt, Reinhold and Seshadri, Sudha and Yang, Qiong and Alvim, Marina K. 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C. and Deary, Ian J. and Delanty, Norman and Depondt, Chantal and Desrivi{\`e}res, Sylvane and Donohoe, Gary and Espeseth, Thomas and Fern{\'a}ndez, Guill{\'e}n and Fisher, Simon E. and Flor, Herta and Forstner, Andreas J. and Francks, Clyde and Franke, Barbara and Glahn, David C. and Gollub, Randy L. and Grabe, Hans J. and Gruber, Oliver and H{\r a}berg, Asta K. and Hariri, Ahmad R. and Hartman, Catharina A. and Hashimoto, Ryota and Heinz, Andreas and Henskens, Frans A. and Hillegers, Manon H. J. and Hoekstra, Pieter J. and Holmes, Avram J. and Hong, L. Elliot and Hopkins, William D. and Hulshoff Pol, Hilleke E. and Jernigan, Terry L. and J{\"o}nsson, Erik G. and Kahn, Ren{\'e} S. and Kennedy, Martin A. and Kircher, Tilo T. J. and Kochunov, Peter and Kwok, John B. J. and Le Hellard, Stephanie and Loughland, Carmel M. and Martin, Nicholas G. and Martinot, Jean-Luc and McDonald, Colm and McMahon, Katie L. and Meyer-Lindenberg, Andreas and Michie, Patricia T. and Morey, Rajendra A. and Mowry, Bryan and Nyberg, Lars and Oosterlaan, Jaap and Ophoff, Roel A. and Pantelis, Christos and Paus, Tom{\'a}{\v s} and Pausova, Zdenka and Penninx, Brenda W. J. H. and Polderman, Tinca J. C. and Posthuma, Danielle and Rietschel, Marcella and Roffman, Joshua L. and Rowland, Laura M. and Sachdev, Perminder S. and S{\"a}mann, Philipp G. and Schall, Ulrich and Schumann, Gunter and Scott, Rodney J. and Sim, Kang and Sisodiya, Sanjay M. and Smoller, Jordan W. and Sommer, Iris E. and St Pourcain, Beate and Stein, Dan J. and Toga, Arthur W. and Trollor, Julian N. and Van der Wee, Nic J. 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