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An Analysis of 15 Polymorphisms in Prior Candidate Genes for Sporadic Alzheimer's Disease

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An Analysis of 15 Polymorphisms in Prior Candidate Genes for Sporadic Alzheimer's Disease European Journal of Human Genetics (2001) 9, 437 ± 444 ã 2001 Nature Publishing Group All rights reserved 1018-4813/01 $15.00 www.nature.com/ejhg ARTICLE Lack of replication of association findings in complex disease: an analysis of 15 polymorphisms in prior candidate genes for sporadic Alzheimer's disease Jonathan A Prince*,1, Lars Feuk1, Sarah L Sawyer1, Johan Gottfries5, Anne Ricksten2, Katarina NaÈgga3, Nenad Bogdanovic4, Kaj Blennow2 and Anthony J Brookes1 1Center for Genomics Research, Karolinska Institute, Stockholm, Sweden; 2Department of Clinical Neuroscience and Transfusion Medicine, University of GoÈteborg, Sahlgren's University Hospital, Sweden; 3Department of Geriatric Medicine, LinkoÈping University Hospital, LinkoÈping, Sweden; 4Department of Clinical Neuroscience and Family Medicine, Section of Geriatric Medicine, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden; 5Department of Medicinal Chemistry, AstraZeneca, MoÈlndal, Sweden There is considerable enthusiasm for the prospect of using common polymorphisms (primarily single nucleotide polymorphisms; SNPs) in candidate genes to unravel the genetics of complex disease. This approach has generated a number of findings of loci which are significantly associated with sporadic Alzheimer's disease (AD). In the present study, a total of 15 genes of interest were chosen from among the previously published reports of significant association in AD. Genotyping was performed on polymorphisms within those genes (14 SNPs and one deletion) using Dynamic Allele Specific Hybridization (DASH) in 204 Swedish patients with sporadic late-onset AD and 186 Swedish control subjects. The genes chosen for analysis were; low-density lipoprotein receptor-related protein (LRP1), angiotensin converting enzyme (DCP1), alpha-2-macroglobulin (A2M), bleomycin hydrolase (BLMH), dihydrolipoyl S-succinyltransferase (DLST), tumour necrosis factor receptor superfamily member 6 (TNFRSF6), nitric oxide synthase (NOS3), presenilin 1 (PSEN1), presenilin 2 (PSEN2), butyrylcholinesterase (BCHE), Fe65 (APBB1), oestrogen receptor alpha (ESR1), cathepsin D (CTSD), methylenetetrahydrofolate reductase (MTHFR), and interleukin 1A (IL1A). We found no strong evidence of association for any of these loci with AD in this population. While the possibility exists that the genes analysed are involved in AD (ie they have weak effects and/or are population specific), results reinforce the need for extensive replication studies if we are to be successful in defining true risk factors in complex diseases. European Journal of Human Genetics (2001) 9, 437 ± 444. Keywords: SNP; DASH; polymorphism; Alzheimer's; sporadic; association Introduction minor fraction of AD cases can be attributed to the autosomal Alzheimer's disease (AD) is a progressive neurodegenerative dominant inheritance of mutations in either amyloid disorder of the elderly with an annual incidence of precursor protein (APP),2 presenilin 1 (PSEN1),3 or presenilin approximately 1% in 65 ± 69 year-olds increasing to about 2 (PSEN2).4,5 Together these may account for as much as 70% 8% in 85 ± 95 year olds.1 Over the past decade, there has been of all early-onset AD cases,6 but this represents only a small considerable effort towards unravelling the genetics of AD. A fraction of all AD cases. The vast majority of individuals afflicted with AD suffer from the non-familial (sporadic) form of the disorder, which is primarily evident in late-onset cases. *Correspondence: Dr JA Prince, Center for Genomics Research, To date, the only well-replicated genetic risk factor for Karolinska Institute, Theorells vaÈg 3, S-171 77 Stockholm, Sweden. sporadic AD is possession of the e4 allele of the gene Tel: +46 8 7286274; Fax: +46 8 331547; E-mail: [email protected] 7±9 Received 21 November 2000; revised 9 February 2001; accepted 7 March encoding apolipoprotein E (APOE). Estimates are that 2001 APOE contributes to anywhere between 30 ± 70% of the total Replicating association findings in Alzheimer's disease JA Prince et al 438 genetic variance in AD.10,11 Thus, a large proportion of the Of the 204 AD cases, 111 had a clinical and 93 a genetic variance in AD must be determined by as yet neuropathological diagnosis. All clinically diagnosed AD unidentified loci. It has been suggested that there may exist patients underwent a thorough investigation, which in- as many as four additional loci with an effect equal or greater cluded a medical history, physical, neurological and psychia- to that of APOE.11 tric examination, screening laboratory tests, ECG, X-ray of There are numerous reports of positive association findings the chest, EEG, and computerised tomography (CT) of the in sporadic AD. The dominant approach has been to employ brain. The diagnosis of `probable AD' was made according to polymorphisms within candidate genes from biological the NINCDS-ADRDA criteria.24 All neuropathologically pathways assumed to be involved in the pathogenesis of diagnosed AD patients also fulfilled the clinical NINCDS- AD. Other than for APOE, significant association findings criteria for probable AD29 and met the neuropathological have been made for; alpha-2-macroglobulin (A2M),12 inter- CERAD criteria for definitive AD.30,31 leukin 1A (IL1a),13,14 angiotensin converting enzyme Of the 186 controls, 76 were healthy volunteers, while 108 (DCP1),15 nitric oxide synthase (NOS3),16 PSEN1,17 PSEN2,18 were autopsy cases. The healthy volunteers were individuals butyrylcholinesterase (BCHE),19 dihydrolipoamide succinyl- without history, symptoms or signs of psychiatric or transferase (DLST),20 Fe65 (APBB1),21 oestrogen receptor- neurological disease, malignant disease, or systemic disor- alpha (ESR1),22 cathepsin D (CTSD),23 low-density lipopro- ders. Cognitive status was examined using MMSE,32 and tein receptor-related protein (LRP1),24 bleomycin hydrolase individuals with scores below 28 were not included as (BLMH)25 and tumour necrosis factor receptor superfamily controls. The autopsy control group consisted of patients member 6 (TNFRSF6).26 who had died from cardiac disease or malignant disease. The chance of identifying risk alleles in complex disease (eg Their medical records revealed no history of dementia, or APOE-e4 in AD) is primarily dependent upon the size of the psychiatric or neurological diseases. Post-mortem examina- effect of a particular gene in that disease and to the size of the tion revealed no macroscopic infarcts, and upon histopatho- population studied. On the basis that most association logical examination low numbers of senile plaques and studies are performed on small to moderate sized single neurofibrillary tangles (NFTs) were found. All autopsy cases populations, the only way to confirm the importance of a risk (AD and control) were matched by age at death and all allele in a disease is by replication. Attempts at replication clinically diagnosed AD cases and healthy volunteers were have been performed on some of these genes, but results have matched by age-at-onset/age-at-exam respectively. in general been negative. The importance of independent replication has also recently been emphasised in response to PCR and choice of polymorphisms the original finding of association with A2M and AD.12,27 PCR primers were designed using Oligo version 5.0 software There are a number of factors which may contribute to the (Molecular Biology Insights, CO, USA) to amplify target inability to reproduce association findings in a complex genomic DNA fragments of 47 ± 60 bp which contained the disease. The results of the original studies may be false polymorphism of interest centered within the product. positives due to population stratification or lack of proper Details of the PCR primer sequences and the sequences of correction for multiple testing. In turn, results in follow up the probes employed for genotyping (see below) are shown in studies may be false negatives due to lack of power and/or Table 1. In 13 of the chosen genes, the polymorphisms differences in ethnic background. In the present study, we originally reported to be associated were genotyped and in have addressed the question of whether or not any of the two genes, different polymorphisms were used. These two aforementioned genes are risk factors for sporadic AD in a latter cases were for DCP1 and PSEN2. For DCP1, a surrogate Swedish population. Considering the strength of the effects was used because of limitations in our genotyping technol- reported in previous studies and given the size of our ogy for scoring large deletions (for which the original report population, this study had 80% power (a=0.05) for detecting was made). In the case of PSEN2, the original report was for a association in any of these genes if they had similar effects in 3'-UTR variant and we chose to focus on an intronic variant. this population. Data for the APOE-e4 allele have been The DCP1 variation used was less than 200 bp from the obtained earlier for this material28 and are therefore included common ALU insertion/deletion and the studied poly- for comparative purposes in this study. morphism for PSEN2 was less than 1 kb from the originally published variation. All oligonucleotides (primers and probes) were ordered from Interactiva GmbH (Germany) Materials and Methods and were supplied after HPLC purification. Clinical materials PCR was performed in 96-well microtiter plates (Corning All patients and controls were of Swedish descent. The AD Costar, NY, USA) on a TouchDown2 temperature cycling group consisted of
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