Peter St George-Hyslop

University of Cambridge, Cambridge, England, United Kingdom

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Publications (457)3733.72 Total impact

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    ABSTRACT: Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes. Hundreds of causative DNA changes have been found, but much of the genetic basis of the disease is still unexplained. Mutations in the ALS5/SPG11/KIAA1840 gene are a frequent cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and peripheral axonal neuropathy, and account for ∼40% of autosomal recessive juvenile amyotrophic lateral sclerosis. The overlap of axonal Charcot-Marie-Tooth disease with both diseases, as well as the common autosomal recessive inheritance pattern of thin corpus callosum and axonal Charcot-Marie-Tooth disease in three related patients, prompted us to analyse the ALS5/SPG11/KIAA1840 gene in affected individuals with autosomal recessive axonal Charcot-Marie-Tooth disease. We investigated 28 unrelated families with autosomal recessive axonal Charcot-Marie-Tooth disease defined by clinical, electrophysiological, as well as pathological evaluation. Besides, we screened for all the known mutations related to axonal autosomal recessive Charcot-Marie-Tooth disease (CMT2A2/HMSN2A2/MFN2, CMT2B1/LMNA, CMT2B2/MED25, CMT2B5/NEFL, ARCMT2F/dHMN2B/HSPB1, CMT2K/GDAP1, CMT2P/LRSAM1, CMT2R/TRIM2, CMT2S/IGHMBP2, CMT2T/HSJ1, CMTRID/COX6A1, ARAN-NM/HINT and GAN/GAN), for the genes related to autosomal recessive hereditary spastic paraplegia with thin corpus callosum and axonal peripheral neuropathy (SPG7/PGN, SPG15/ZFYVE26, SPG21/ACP33, SPG35/FA2H, SPG46/GBA2, SPG55/C12orf65 and SPG56/CYP2U1), as well as for the causative gene of peripheral neuropathy with or without agenesis of the corpus callosum (SLC12A6). Mitochondrial disorders related to Charcot-Marie-Tooth disease type 2 were also excluded by sequencing POLG and TYMP genes. An additional locus for autosomal recessive Charcot-Marie-Tooth disease type 2H on chromosome 8q13-21.1 was excluded by linkage analysis. Pedigrees originated in Italy, Brazil, Canada, England, Iran, and Japan. Interestingly, we identified 15 ALS5/SPG11/KIAA1840 mutations in 12 families (two sequence variants were never reported before, p.Gln198* and p.Pro2212fs*5). No large deletions/duplications were detected in these patients. The novel mutations seemed to be pathogenic since they co-segregated with the disease in all pedigrees and were absent in 300 unrelated controls. Furthermore, in silico analysis predicted their pathogenic effect. Our results indicate that ALS5/SPG11/KIAA1840 is the causative gene of a wide spectrum of clinical features, including autosomal recessive axonal Charcot-Marie-Tooth disease.
    Full-text · Article · Nov 2015 · Brain
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    ABSTRACT: IMPORTANCE: Mutations in known causal Alzheimer disease (AD) genes account for only 1% to 3%of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays. OBJECTIVE: To evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals. DESIGN, SETTING, AND PARTICIPANTS: Case-control study of a large African American data set previously genotyped on different genome-wide SNP arrays conducted from December 2013 to January 2015. Global and locus-basedROHmeasurementswere analyzed using rawor imputed genotype data.We studied the rawgenotypes from 2 case-control subsets grouped based on SNP array: Alzheimer's Disease Genetics Consortium data set (871 cases and 1620control individuals) and Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set (279 cases and 1367 control individuals).We then examined the entire data set using imputed genotypes from 1917 cases and 3858 control individuals. MAIN OUTCOMES AND MEASURES: The ROHs larger than 1Mb, 2Mb, or 3Mb were investigated separately for global burden evaluation, consensus regions, and gene-based analyses. RESULTS: The African American cohort had a lowdegree of inbreeding (F × 0.006). In the Alzheimer's Disease Genetics Consortium data set, we detected a significantly higher proportion of cases with ROHs greater than 2Mb (P =.004) or greater than 3Mb (P =.02), aswell as a significant 114-kilobase consensus region on chr4q31.3 (empirical P value 2 =.04; ROHs >2 Mb). In the Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set, we identified a significant 202-kilobase consensus region on Chr15q24.1 (empirical P value 2 =.02; ROHs >1 Mb) and a cluster of 13 significant genes on Chr3p21.31 (empirical P value 2 =.03; ROHs >3 Mb). Atotal of 43 of 49 nominally significant genescommonfor both data sets also mapped to Chr3p21.31. Analyses of imputed SNP data from the entire data set confirmed the association of AD with global ROH measurements (12.38 ROHs >1Mb in cases vs 12.11 in controls; 2.986Mb average size of ROHs >2Mb in cases vs 2.889Mb in controls; and 22%of cases with ROHs >3Mb vs 19% of controls) and a gene-cluster on Chr3p21.31 (empirical P value 2 =.006-.04; ROHs >3 Mb). Also, we detected a significant association between AD and CLDN17 (empirical P value 2 =.01; ROHs >1 Mb), encoding a protein from the Claudin family, members of whichwere previously suggested as ADbiomarkers. CONCLUSIONS AND RELEVANCE: To our knowledge, we discovered the first evidence of increased burden of ROHs among patients with AD from an outbred African American population, which could reflect either the cumulative effect of multiple ROHs to AD or the contribution of specific loci harboring recessive mutations and risk haplotypes in a subset of patients. Sequencing is required to uncover AD variants in these individuals.
    Full-text · Article · Nov 2015
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    Full-text · Dataset · Nov 2015
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    ABSTRACT: The similarities between Dementia with Lewy Bodies (DLB) and both Parkinson’s (PD) and Alzheimer’s disease (AD) are many and range from clinical presentation, to neuropathological characteristics, to more recently identified, genetic determinants of risk. Because of these overlapping features, diagnosing DLB is challenging and has clinical implications since some therapeutic agents that are applicable in other diseases have adverse effects in DLB. Having shown that DLB shares some genetic risk with PD and AD, we have now quantified the amount of sharing through the application of genetic correlation estimates, and show that, from a purely genetic perspective, and excluding the strong association at the APOE locus, DLB is equally correlated to AD and PD.
    Full-text · Article · Nov 2015 · Neurobiology of Aging
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    ABSTRACT: The mechanisms by which mutations in FUS and other RNA binding proteins cause ALS and FTD remain controversial. We propose a model in which low-complexity (LC) domains of FUS drive its physiologically reversible assembly into membrane-free, liquid droplet and hydrogel-like structures. ALS/FTD mutations in LC or non-LC domains induce further phase transition into poorly soluble fibrillar hydrogels distinct from conventional amyloids. These assemblies are necessary and sufficient for neurotoxicity in a C. elegans model of FUS-dependent neurodegeneration. They trap other ribonucleoprotein (RNP) granule components and disrupt RNP granule function. One consequence is impairment of new protein synthesis by cytoplasmic RNP granules in axon terminals, where RNP granules regulate local RNA metabolism and translation. Nuclear FUS granules may be similarly affected. Inhibiting formation of these fibrillar hydrogel assemblies mitigates neurotoxicity and suggests a potential therapeutic strategy that may also be applicable to ALS/FTD associated with mutations in other RNA binding proteins.
    Full-text · Article · Oct 2015 · Neuron
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    ABSTRACT: A potential strategy to alleviate the aggregation of intrinsically disordered proteins (IDPs) is to maintain the native functional state of the protein by small molecule binding. However, the targeting of the native state of IDPs by small molecules has been challenging due to their heterogeneous conformational ensembles. To tackle this challenge, we applied a high-throughput chemical microarray surface plasmon resonance imaging screen to detect the binding between small molecules and monomeric full-length Tau, a protein linked with the onset of a range of Tauopathies. The screen identified a novel set of drug-like fragment and lead-like compounds that bound to Tau. We verified that the majority of these hit compounds reduced the aggregation of different Tau constructs in vitro and in N2a cells. These results demonstrate that Tau is a viable receptor of drug-like small molecules. The drug discovery approach that we present can be applied to other IDPs linked to other misfolding diseases such as Alzheimer’s and Parkinson’s diseases.
    No preview · Article · Oct 2015 · Current Alzheimer Research
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    ABSTRACT: Background: Mutations in the SPG11/KIAA1840 gene are common cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and peripheral axonal neuropathy and accounts for about 40% of autosomal recessive juvenile amyotrophic lateral sclerosis. The overlap between axonal Charcot-Marie-Tooth disease and both these diseases, as well as the common autosomal recessive inherited findings of thin corpus callosum and axonal Charcot-Marie-Tooth in three related patients, prompted us to sequence the SPG11/KIAA1840 gene in affected individuals with autosomal recessive axonal Charcot-Marie-Tooth disease. Methods: The study focused on 28 unrelated pedigrees with autosomal recessive Charcot-Marie-Tooth type 2 and without genetic assessment, originated in Italy, Brazil, Canada, England, Iran, and Japan. The diagnosis was based on clinical findings and familiar history. Clinical and instrumental functional analysis consist of neurological assessment, diagnostic imaging, electroneurographic assay, and sural nerve biopsy. Molecular studies include linkage analysis, Sanger sequencing, RFLP analysis and bioinformatics. Results: Linkage study of all families showed homozygous haplotypes and produced positive logarithm of odds score in all affected subjects. Sanger sequencing identified 15 SPG11/KIAA1840 mutations in 12 families. Two sequence changes were never reported before and in silico analysis predicted their pathogenetic effect. All mutations seemed to be pathogenic since they co-segregated with the disease in all pedigree and were absent in controls. All known axonal Charcot-Marie-Tooth autosomal recessive loci (CMT1F/CMT2E/ NEFL, CMT2A/CMT2B1/LMNA, CMT2A2/MFN2, CMT2B2/MED25, CMT2F/HSPB1/HSP27, CMT2K/GDAP1, CMT2P/LRSAM1, CMT4C/ KIAA1985, CMTRID/COX6A1, NMAN/HINT), genes causing autosomal recessive hereditary spastic paraplegia with thin corpus callosum and axonal peripheral neuropathy (SPG7, SPG15, and SPG21), as well as the causative gene of peripheral neuropathy with or without agenesis of the corpus callosum (SLC12A6) were screened out. An additional locus for autosomal recessive Charcot-Marie-Tooth disease type 2H on chromosome 8q13-21. 1 was excluded by linkage analysis. Conclusions: Our results indicate that SPG11/KIAA1840 is the causative gene of a wide spectrum of clinical features, including autosomal recessive axonal Charcot-Marie-Tooth disease.
    Full-text · Conference Paper · Oct 2015
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    ABSTRACT: The mechanisms by which mutations in FUS and other RNA binding proteins cause ALS and FTD remain controversial. We propose a model in which low-complexity (LC) domains of FUS drive its physiologically reversible assembly into membrane-free, liquid droplet and hydrogel-like structures. ALS/FTD mutations in LC or non-LC domains induce further phase transition into poorly soluble fibrillar hydrogels distinct from conventional amyloids. These assemblies are necessary and sufficient for neurotoxicity in a C. elegans model of FUS-dependent neurodegeneration. They trap other ribonucleoprotein (RNP) granule components and disrupt RNP granule function. One consequence is impairment of new protein synthesis by cytoplasmic RNP granules in axon terminals, where RNP granules regulate local RNA metabolism and translation. Nuclear FUS granules may be similarly affected. Inhibiting formation of these fibrillar hydrogel assemblies mitigates neurotoxicity and suggests a potential therapeutic strategy that may also be applicable to ALS/FTD associated with mutations in other RNA binding proteins.
    Full-text · Article · Oct 2015 · Neuron
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    ABSTRACT: Importance Mutations in known causal Alzheimer disease (AD) genes account for only 1% to 3% of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays.Objective To evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals.Design, Setting, and Participants Case-control study of a large African American data set previously genotyped on different genome-wide SNP arrays conducted from December 2013 to January 2015. Global and locus-based ROH measurements were analyzed using raw or imputed genotype data. We studied the raw genotypes from 2 case-control subsets grouped based on SNP array: Alzheimer’s Disease Genetics Consortium data set (871 cases and 1620 control individuals) and Chicago Health and Aging Project–Indianapolis Ibadan Dementia Study data set (279 cases and 1367 control individuals). We then examined the entire data set using imputed genotypes from 1917 cases and 3858 control individuals.Main Outcomes and Measures The ROHs larger than 1 Mb, 2 Mb, or 3 Mb were investigated separately for global burden evaluation, consensus regions, and gene-based analyses.Results The African American cohort had a low degree of inbreeding (F ~ 0.006). In the Alzheimer’s Disease Genetics Consortium data set, we detected a significantly higher proportion of cases with ROHs greater than 2 Mb (P = .004) or greater than 3 Mb (P = .02), as well as a significant 114-kilobase consensus region on chr4q31.3 (empirical P value 2 = .04; ROHs >2 Mb). In the Chicago Health and Aging Project–Indianapolis Ibadan Dementia Study data set, we identified a significant 202-kilobase consensus region on Chr15q24.1 (empirical P value 2 = .02; ROHs >1 Mb) and a cluster of 13 significant genes on Chr3p21.31 (empirical P value 2 = .03; ROHs >3 Mb). A total of 43 of 49 nominally significant genes common for both data sets also mapped to Chr3p21.31. Analyses of imputed SNP data from the entire data set confirmed the association of AD with global ROH measurements (12.38 ROHs >1 Mb in cases vs 12.11 in controls; 2.986 Mb average size of ROHs >2 Mb in cases vs 2.889 Mb in controls; and 22% of cases with ROHs >3 Mb vs 19% of controls) and a gene-cluster on Chr3p21.31 (empirical P value 2 = .006-.04; ROHs >3 Mb). Also, we detected a significant association between AD and CLDN17 (empirical P value 2 = .01; ROHs >1 Mb), encoding a protein from the Claudin family, members of which were previously suggested as AD biomarkers.Conclusions and Relevance To our knowledge, we discovered the first evidence of increased burden of ROHs among patients with AD from an outbred African American population, which could reflect either the cumulative effect of multiple ROHs to AD or the contribution of specific loci harboring recessive mutations and risk haplotypes in a subset of patients. Sequencing is required to uncover AD variants in these individuals.
    Full-text · Article · Sep 2015 · JAMA Neurology
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    ABSTRACT: Progressive supranuclear palsy (PSP) is a movement disorder characterized by tau neuropathology where the underlying mechanism is unknown. An SNP (rs1768208 C/T) has been identified as a strong risk factor for PSP. Here, we identified a much higher T-allele occurrence and increased levels of the pro-apoptotic protein appoptosin in PSP patients. Elevations in appoptosin correlate with activated caspase-3 and caspase-cleaved tau levels. Appoptosin overexpression increased caspase-mediated tau cleavage, tau aggregation, and synaptic dysfunction, whereas appoptosin deficiency reduced tau cleavage and aggregation. Appoptosin transduction impaired multiple motor functions and exacerbated neuropathology in tau-transgenic mice in a manner dependent on caspase-3 and tau. Increased appoptosin and caspase-3-cleaved tau were also observed in brain samples of patients with Alzheimer's disease and frontotemporal dementia with tau inclusions. Our findings reveal a novel role for appoptosin in neurological disorders with tau neuropathology, linking caspase-3-mediated tau cleavage to synaptic dysfunction and behavioral/motor defects. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Sep 2015 · Neuron

  • No preview · Article · Aug 2015 · Alzheimer's & dementia: the journal of the Alzheimer's Association
  • Kanayo Satoh · Sumiko Abe-Dohmae · Shinji Yokoyama · Peter St George-Hyslop · Paul E Fraser
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    ABSTRACT: The ATP-binding cassette transporter A7 (ABCA7) has been identified as a susceptibility factor of late-onset Alzheimer's disease (LOAD) in Genome Wide Association Studies (GWAS). ABCA7 has been shown to mediate phagocytosis and affects membrane trafficking. The current study examines the impact of ABCA7 loss-offunction on amyloid precursor protein (APP) processing and generation of amyloid-β (Aβ). Suppression of endogenous ABCA7 in several different cell lines resulted in increased β-secretase cleavage and elevated Aβ. ABCA7 knockout mice displayed an increased production of endogenous murine amyloid Aβ42 species. Crossing ABCA7 deficient animals to an APP transgenic model resulted in significant increases in the soluble Aβ as compared to mice expressing normal levels of ABCA7. Only modest changes in the amount of insoluble Aβ and amyloid plaque densities were observed once the amyloid pathology was well developed while Aβ deposition was enhanced in younger animals. In vitro studies indicated a more rapid endocytosis of APP in ABCA7 knockout cells that is mechanistically consistent with the increased Aβ production. These in vitro and in vivo findings indicate a direct role of ABCA7 in amyloid processing, which may be associated with its primary biological function to regulate endocytic pathways. Several potential loss-of-function ABCA7 mutations and deletions linked to AD have recently been identified which, in some instances, have a great impact than ApoE allelic variants. A reduction in ABCA7 expression or loss of function would be predicted to increase amyloid production and that may be a contributing factor in the associated AD susceptibility. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    No preview · Article · Aug 2015 · Journal of Biological Chemistry

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  • No preview · Article · Jul 2015
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    ABSTRACT: To detect rare coding variants underlying loci detected by genome-wide association studies (GWASs) of late-onset Alzheimer's disease (LOAD). We conducted targeted sequencing of ABCA7, BIN1, CD2AP, CLU, CR1, EPHA1, MS4A4A/MS4A6A and PICALM in three independent LOAD cohorts: 176 patients from 124 Caribbean Hispanics families, 120 patients and 33 unaffected individuals from the 129 NIA-LOAD Family Study; and 263 unrelated Canadian individuals of European ancestry (210 sporadic patients and 53 controls). Rare coding variants found in at least two datasets were genotyped in independent groups of ancestry matched controls. Additionally, the Exome Aggregation Consortium (ExAC) was used as a reference dataset for population-based allele frequencies. Overall we detected a statistically significant 3.1-fold enrichment of the non-synonymous mutations in the Caucasian LOAD cases compared with controls (p=0.002) and no difference in synonymous variants. A stopgain mutation in ABCA7 (E1769X) and missense mutation in CD2AP (T374A) were highly significant in Caucasian LOAD cases, and mutations in EPHA1 (P460L) and BIN1 (K358R) were significant in Caribbean Hispanic families with LOAD. The EPHA1 variant segregated completely in an extended Caribbean Hispanic family and was also nominally significant in the Caucasians. Additionally, BIN1 (K358R) segregated in two of the six Caribbean Hispanic families where the mutations were discovered. Targeted sequencing of confirmed GWAS loci revealed an excess burden of deleterious coding mutations in LOAD with the greatest burden observed in ABCA7 and BIN1. Identifying coding variants in LOAD will facilitate the creation of tractable models for investigation of disease related mechanisms and potential therapies. This article is protected by copyright. All rights reserved. © 2015 American Neurological Association.
    No preview · Article · Jun 2015 · Annals of Neurology
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    ABSTRACT: The acute neurotoxicity of oligomeric forms of amyloid-β 1-42 (Aβ) is implicated in the pathogenesis of Alzheimer's disease (AD). However, how these oligomers might first impair neuronal function at the onset of pathology is poorly understood. Here we have examined the underlying toxic effects caused by an increase in levels of intracellular Aβ, an event that could be important during the early stages of the disease. We show that oligomerised Aβ induces a rapid enhancement of AMPA receptor-mediated synaptic transmission (EPSCA) when applied intracellularly. This effect is dependent on postsynaptic Ca(2+) and PKA. Knockdown of GluA1, but not GluA2, prevents the effect, as does expression of a S845-phosphomutant of GluA1. Significantly, an inhibitor of Ca(2+)-permeable AMPARs (CP-AMPARs), IEM 1460, reverses the increase in the amplitude of EPSCA. These results suggest that a primary neuronal response to intracellular Aβ oligomers is the rapid synaptic insertion of CP-AMPARs.
    Full-text · Article · Jun 2015 · Scientific Reports
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    ABSTRACT: Objective In the context of late-onset Alzheimer's disease (LOAD) over 20 genes have been identified but, aside APOE, all show small effect sizes, leaving a large part of the genetic component unexplained. Admixed populations, such as Caribbean Hispanics, can provide a valuable contribution because of their unique genetic profile and higher incidence of the disease. We aimed to identify novel loci associated with LOAD.Methods About 4514 unrelated Caribbean Hispanics (2451 cases and 2063 controls) were selected for genome-wide association analysis. Significant loci were further tested in the expanded cohort that also included related family members (n = 5300). Two AD-like transgenic mice models (J20 and rTg4510) were used to study gene expression. Independent data sets of non-Hispanic Whites and African Americans were used to further validate findings, along with publicly available brain expression data sets.ResultsA novel locus, rs75002042 in FBXL7 (5p15.1), was found genome-wide significant in the case–control cohort (odd ratio [OR] = 0.61, P = 6.19E-09) and confirmed in the related members cohorts (OR = 0.63, P = 4.7E-08). Fbxl7 protein was overexpressed in both AD-like transgenic mice compared to wild-type littermates. Publicly available microarray studies also showed significant overexpression of Fbxl7 in LOAD brains compared to nondemented controls. single-nucleotide polymorphism (SNP) rs75002042 was in complete linkage disequilibrium with other variants in two independent non-Hispanic White and African American data sets (0.0005 < P < 0.02) used for replication.InterpretationFBXL7, encodes a subcellular protein involved in phosphorylation-dependent ubiquitination processes and displays proapoptotic activity. F-box proteins also modulate inflammation and innate immunity, which may be important in LOAD pathogenesis. Further investigations are needed to validate and understand its role in this and other populations.
    Full-text · Article · Jun 2015

  • No preview · Article · Mar 2015 · Brain
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    ABSTRACT: APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P⩽1.3 × 10(-8)), frontal cortex (P⩽1.3 × 10(-9)) and temporal cortex (P⩽1.2 × 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10(-6)) and temporal cortex (P=2.6 × 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.Molecular Psychiatry advance online publication, 17 March 2015; doi:10.1038/mp.2015.23.
    Full-text · Article · Mar 2015 · Molecular Psychiatry

Publication Stats

30k Citations
3,733.72 Total Impact Points

Institutions

  • 2009-2015
    • University of Cambridge
      • Department of Clinical Neurosciences
      Cambridge, England, United Kingdom
    • Columbia University
      • Gertrude H. Sergievsky Center
      New York, New York, United States
  • 1991-2015
    • University of Toronto
      • • Department of Medical Biophysics
      • • Tanz Centre for Research in Neurodegenerative Diseases
      • • Department of Medicine
      • • Department of Pharmacology and Toxicology
      • • Division of Neurology
      Toronto, Ontario, Canada
    • National Institute on Aging
      • Laboratory of Neurosciences (LNS)
      Baltimore, Maryland, United States
  • 2013
    • Cambridge Institute for Medical Research
      Cambridge, England, United Kingdom
  • 2012
    • University of Alberta
      • Centre for Prions and Protein Folding Diseases
      Edmonton, Alberta, Canada
  • 2006
    • University of Nice-Sophia Antipolis
      • Institut de Pharmacologie Moléculaire et Cellulaire (IPMC/UMR6097 CNRS-UNS)
      Nice, Provence-Alpes-Côte d'Azur, France
  • 2001-2006
    • University Health Network
      • • Department of Medicine
      • • Division of Nephrology
      Toronto, Ontario, Canada
  • 1998-2006
    • University of Florence
      Florens, Tuscany, Italy
    • Mount Sinai Hospital, Toronto
      • Department of Medical Imaging
      Toronto, Ontario, Canada
    • University of Miami Miller School of Medicine
      • Department of Psychiatry and Behavioral Sciences
      Miami, Florida, United States
    • University of Guadalajara
      Guadalajara, Jalisco, Mexico
  • 2005
    • University of Ottawa
      Ottawa, Ontario, Canada
  • 2004
    • University of Rome Tor Vergata
      Roma, Latium, Italy
    • University of Texas at Dallas
      Richardson, Texas, United States
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 2002
    • University of Antwerp
      • VIB Department of Molecular Genetics
      Antwerpen, VLG, Belgium
  • 2000-2002
    • Toronto Western Hospital
      Toronto, Ontario, Canada
  • 1992
    • University of California, Los Angeles
      • Department of Neurology
      Los Ángeles, California, United States
  • 1990
    • Medical Neurogenetics
      Atlanta, Georgia, United States
  • 1988-1990
    • Harvard Medical School
      • • Department of Neurology
      • • Department of Genetics
      Boston, Massachusetts, United States
  • 1987-1989
    • Harvard University
      Cambridge, Massachusetts, United States
    • Massachusetts General Hospital
      • Neuroepigenetics Laboratory
      Boston, MA, United States