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Multiple Loci Influencing Hippocampal Degeneration Identified by Genome Scan

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Multiple Loci Influencing Hippocampal Degeneration Identified by Genome Scan RAPID COMMUNICATION Multiple Loci Influencing Hippocampal Degeneration Identified by Genome Scan Scott A. Melville, PhD,1 Jacqueline Buros, BA,1 Antonio R. Parrado, PhD,2,3 Badri Vardarajan, MS,1 Mark W. Logue, PhD,1 Li Shen, PhD,4 Shannon L. Risacher, PhD,4 the Alzheimer’s Disease Neuroimaging Initiative, Sungeun Kim, PhD,4 Gyungah Jun, PhD,1,5,6 Charles DeCarli, MD,7 Kathryn L. Lunetta, PhD,6 Clinton T. Baldwin, PhD,1,8 Andrew J. Saykin, PhD,4 and Lindsay A. Farrer, PhD1,5,6,9,10 Objective: Large genome-wide association studies (GWASs) have identified many novel genes influencing Alzheimer disease (AD) risk, but most of the genetic variance remains unexplained. We conducted a 2-stage GWAS for AD- related quantitative measures of hippocampal volume (HV), total cerebral volume (TCV), and white matter hyperintensities (WMH). Methods: Brain magnetic resonance imaging measures of HV, TCV, and WMH were obtained from 981 Caucasian and 419 African American AD cases and their cognitively normal siblings in the MIRAGE (Multi Institutional Research in Alzheimer’s Genetic Epidemiology) Study, and from 168 AD cases, 336 individuals with mild cognitive impairment, and 188 controls in the Alzheimer’s Disease Neuroimaging Initiative Study. A GWAS for each trait was conducted in the 2 Caucasian data sets in stage 1. Results from the 2 data sets were combined by meta-analysis. In stage 2, 1 single nucleotide polymorphism (SNP) from each region that was nominally significant in each data set (p < 0.05) À and strongly associated in both data sets (p < 1.0 Â 10 5) was evaluated in the African American data set. Results: Twenty-two markers (14 for HV, 3 for TCV, and 5 for WMH) from distinct regions met criteria for evaluation À in stage 2. Novel genome-wide significant associations (p < 5.0 Â 10 8) were attained for HV with SNPs in the APOE, F5/SELP, LHFP, and GCFC2 gene regions. All of these associations were supported by evidence in each data À À set. Associations with different SNPs in the same gene (p < 1 Â 10 5 in Caucasians and p < 2.2 Â 10 4 in African Americans) were also observed for PICALM with HV, SYNPR with TCV, and TTC27 with WMH. Interpretation: Our study demonstrates the efficacy of endophenotypes for broadening our understanding of the genetic basis of AD. ANN NEUROL 2012;72:65–75 ifficulties in the search for susceptibility genes for inherited risk of AD.3 Heritable AD-related endopheno- DAlzheimer disease (AD) have been attributed to the types obtained by magnetic resonance imaging (MRI) etiological heterogeneity of the clinically defined disease provide in vivo measures of neurodegenerative and cere- phenotype.1 Genome-wide association studies (GWASs) brovascular brain injury and can serve as intermediate using very large samples have increased the number of phenotypes for genetic studies of AD.4 The heritability robust associations to 10 genes, including APOE1–3; for hippocampal volume (HV) and white matter hyper- however, these loci account for no more than 35% of the intensities (WMH) is 0.40 and 0.73, respectively, among View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.23644 Received Feb 28, 2012, and in revised form Apr 17, 2012. Accepted for publication May 9, 2012. Address correspondence to Dr Farrer, Biomedical Genetics L320, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118. E-mail: [email protected] A complete list of Alzheimer’s Disease Neuroimaging Initiative investigators can be found at http://adni.loni.ucla.edu/wp-content/uploads/ how_to_apply/ADNI_Acknowledgement_List.pdf From the 1Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA; 2Genetics and Aging Research Unit, Massachusetts General Hospital, Boston, MA; 3Department of Neurology, Harvard Medical School, Boston, MA; 4Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN; 5Department of Ophthalmology, Boston University School of Medicine, Boston, MA; 6Department of Epidemiology, Boston University School Public Health, Boston, MA; 7Department of Neurology, University of California at Davis, Davis, CA; 8Center for Human Genetics, Boston University School of Medicine, Boston, MA; 9Department of Neurology, Boston University School of Medicine, Boston, MA; and 10Department of Biostatistics, Boston University School of Public Health, Boston, MA. Additional supporting information can be found in the online version of this article. VC 2012 American Neurological Association 65 ANNALS of Neurology TABLE 1: Characteristics of Study Cohorts MIRAGE African ADNI MIRAGE Caucasian American Characteristic AD MCI CON AD CON AD CON Sample size 168 336 188 454 537 188 231 % female 0.536 0.643 0.559 0.602 0.604 0.670 0.707 Age at baseline MRI, 75.4 6 7.6 75.2 6 7.1 75 6 4.9 73.2 6 8.3 69 6 8.7 74.7 69.4 68.4 6 10.2 mean yr 6 SD APOE e4 allele frequency 0.420 0.342 0.144 0.291 0.194 0.335 0.205 AD ¼ Alzheimer disease; ADNI ¼ Alzheimer’s Disease Neuroimaging Initiative; CON ¼ cognitively healthy control; MCI ¼ mild cognitive impairment; MIRAGE ¼ Multi Institutional Research in Alzheimer’s Genetic Epidemiology; MRI ¼ magnetic resonance imaging; SD ¼ standard deviation. elderly male twins,5,6 and MRI measures of cerebrovascu- ment site. Characteristics of the ADNI and MIRAGE subjects lar disease and neurodegeneration are highly heritable in included in this study are summarized in Table 1. AD families.4 Candidate gene studies have revealed genetic associa- MRI Traits tions with several AD-related MRI traits. Cortical structural In the MIRAGE sample, magnetic resonance images of the changes are associated with specific APOE genotypes among brain were obtained with 1.5T magnetic field strength scanners using a standard protocol of a 3-dimensional T1-weighted nondemented elderly, as 4carriershavedemonstrably high-resolution sequence, a double spin-echo sequence, and a smaller hippocampal volumes than non-4carriers.7 One fluid attenuated inversion recovery sequence. Semiquantitative study observed a correspondence of single nucleotide poly- measures of bilateral medial temporal (hippocampal) volume morphisms (SNPs) and haplotypes from the 2 AD-associ- (HV), total cerebral volume (TCV), and WMH were obtained SORL1 ated regions of with MRI and neuropathological from these scans and using methods previously described, which 8 measures of WMH and HV. Association of HV with sev- account for total intracranial volume.18 These measures were eral variants and haplotypes in the TTR gene has also been designed to be simple to use and have been shown to linearly reported.9 GWASs of structural and volumetric changes10– correlate with image quantification.19 MRI scans were evaluated 13 and using a voxel-based approach14 confirmed SNPs in by a single rater blinded to age, gender, and affection status to the APOE and TOMM40 genes as markers strongly associ- reduce inter-rater variability common to semiquantitative meth- ated with multiple brain regions including the amygdala ods. TCV and WMH were rated on a scale of 0 to 100. HV p < was rated on an ordinal scale of 0 to 4 according to previously and hippocampus, and yielded promising findings ( 20 À described methods. TCV and HV were scored as damage 10 6) with several other genes (reviewed in Weiner et al15). expressed as a percentage of the overall brain volume. WMH In this paper, we report results from a GWAS for 3 scores were log10 transformed. AD-related MRI measures in a multiethnic sample. Brain MRI scans (1.5T) were obtained from ADNI sub- jects as described elsewhere.21 Available longitudinal scans were also analyzed (Supplementary Table 1). TCV and HV were Subjects and Methods measured at the baseline visit and 12 months later using Free- Subjects Surfer (http://surfer.nmr.mgh.harvard.edu/), an open source One group of subjects are participants of the Multi Institutional program that converts MRI data into volumetric measures.11 Research in Alzheimer’s Genetic Epidemiology (MIRAGE) WMH volume was measured at 0, 6, 12, 18, 24, and 36 Study, a family-based genetic epidemiological study of AD months. To obtain a normal distribution for analysis, an adjust- described in detail elsewhere (http://www.adni-info.org).16 A ment value of 0.5 was added and then log10 transformed. second sample was obtained from the Alzheimer’s Disease Neu- roimaging Initiative (ADNI) Study. Brain imaging, biological Genotyping, Quality Control Procedures, and samples, and clinical assessments were longitudinally collected Imputation for healthy controls and patients with mild cognitive decline ADNI participants and approximately 2=3 of the MIRAGE sub- (MCI) and AD. Details regarding subject ascertainment and jects were genotyped on the Illumina (San Diego, CA) Infinium evaluation have been previously described.17 Study protocols Human 610-Quad BeadChip. The remaining MIRAGE sub- were approved by institutional review boards at each recruit- jects were genotyped with the Illumina Infinium 66 Volume 72, No. 1 Melville et al: AD-Related MRI Traits HUmanCNV370-Duo BeadChip. Genotyping for the APOE implemented in the GEEPACK package within the R statistical 2/3/4 alleles was performed in the MIRAGE data set using a programming language (version 12.2.1)27 were used to account Roche Diagnostics (Mannheim, Germany) LightCycler 480 for the MIRAGE family-based design and repeated measures in instrument. APOE genotypes in the ADNI cohort were the ADNI data set. SNP association results obtained from the obtained by pyrosequencing or restriction fragment length poly- ADNI and MIRAGE data sets were combined by meta-analysis morphism analysis. using the z score method in METAL.28 Prior to analysis, SNPs with a call rate <98%, with a In the stage 1 analysis, SNPs attaining a meta-analysis p À minor allele frequency (MAF) <0.05 or not in Hardy–Weinberg value <1 Â 10 5 and at least nominal significance (p < 0.05) À equilibrium (HWE; p < 10 6) among unaffected, unrelated in both Caucasian data sets were identified as threshold SNPs.
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