Genetic variation in the choline O-acetyltransferase gene in ...

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Journal of Psychiatric Research 45 (2011) 1250e1256

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Genetic variation in the choline O-acetyltransferase gene in depression and Alzheimer’s disease: The VITA and Milano studies Edna Grünblatt a, b, g, *, 2, Andreas Reif b, 2, Susanne Jungwirth a, Daniela Galimberti c, Heike Weber b, Elio Scarpini c, Cathrin Sauer d, Ildiko Wichart a, Michael K. Rainer a, Klaus Huber e, Walter Danielczyk a, Karl H. Tragl a, Jürgen Deckert b, Peter Fischer a, f,1, Peter Riederer a, b,1 a

Ludwig Boltzmann Society, L. Boltzmann Institute of Aging Research, Vienna, Austria Department of Psychiatry, Psychosomatic and Psychotherapy, University Hospital of Würzburg, Füchsleinstr. 15, D-97080 Würzburg, Germany Department of Neurological Sciences, “Dino Ferrari” Center, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico Milan, Italy d Center for Clinical Studies, University Hospital of Würzburg, Josef-Schneider-Str. 2, D-97080 Würzburg, Germany e Institute of Laboratory Medicine, Department of Molecular Biology, Social Medicine Center East e Donauspital, Langobardenstraße 122, A-1220 Vienna, Austria f Department of Psychiatry, Social Medicine Center East e Donauspital, Langobardenstraße 122, A-1220 Vienna, Austria g University of Zürich, Department of Child and Adolescent Psychiatry, Neumünsterallee 9, CH-8032 Zurich, Switzerland b c

a r t i c l e i n f o

a b s t r a c t

Article history: Received 29 October 2010 Received in revised form 25 March 2011 Accepted 28 March 2011

Linkage studies point to the long arm of chromosome 10 being a susceptibility region for Alzheimer’s disease (AD). Additionally, the gene choline O-acetyltransferase (CHAT) located on chromosome 10 was discussed for conveying risk towards AD, but the results are ambiguous. We examined a possible association of nineteen single-nucleotide polymorphisms (SNPs) in the CHAT gene in a longitudinal cohort study, the Vienna Tansdanube Aging (VITA)-study, in which all subjects were 75 years old at baseline. For replication, we used a more heterogeneous case-control sample from Milano with early and late AD. Nominal allelic and genotypic associations with AD risk in the cross-sectional VITA sample were found for rs3810950 (p ¼ 0.038 for genotype, OR ¼ 1.66 95% CI 1.03e2.68, p ¼ 0.052 allele-wise). When combining both VITA- and Milano study rs3810950 was significantly associated with AD (pcombined ¼ 0.01634; power ¼ 82%). This association was highly significant for APOEe4 carriers (p ¼ 0.009 for genotype, OR ¼ 3.21 95% CI 1.43e7.19 p ¼ 0.007 allele-wise). Furthermore, an association of rs1880676 with AD was specific to carriers of the APOEe4 risk allele (p ¼ 0.008, genotype; OR ¼ 3.47 95% CI 1.50e8.01 p ¼ 0.005 allele-wise). For depressive symptoms, we found a nominally significant association of rs3810950 with minor and major depression (p ¼ 0.023, genotype; p ¼ 0.008, allele). Applying Benjamini and Hochberg correction these associations could not be confirmed and also not be replicated in the more heterogeneous Milano sample. While our data therefore do not seem to support a major role for CHAT genetic variation in geriatric depression and AD, there might be a minor contribution in geriatric patients with depression and late onset AD, in particular those carrying the APOEe4 genotype. Ó 2011 Elsevier Ltd. All rights reserved.

Keywords: Alzheimer’s disease Choline acetyltransferase Dementia Depression Haplotype Polymorphism

1. Introduction Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized pathologically by extensive neuronal cell loss (in particular within the hippocampus and neocortex) and by the accumulation of both senile plaques containing b-amyloid and of

* Corresponding author. University of Zürich, Department of Child and Adolescent Psychiatry, Neumünsterallee 9, CH-8032 Zurich, Switzerland. Tel.: þ41 43 556 4002; fax: þ41 43 556 4005. E-mail address: [email protected] (E. Grünblatt). 1 Both authors equally entitled as last author. 2 Both authors equally entitled as first author. 0022-3956/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.jpsychires.2011.03.017

neurofibrillary tangles (NFTs) containing abnormally-phosphorylated tau protein (Chapman et al., 2001). Thus far, autosomal dominant mutations have been identified in three separate genes which contribute to autosomal early onset forms of this disease: amyloid precursor protein, presenilin 1 and presenilin 2 (Di Fede et al., 2009; Serretti et al., 2007), which account for an estimated 3e5% of all AD cases. Predominantly, this disease has late onset (>65 years of age) and does not show a clear Mendelian pattern of segregation. However, genetic factors play an important role in determining late onset AD (LOAD) risk. The apolipoprotein E (APOE) gene e4 allele is the only known genetic variant that is unequivocally associated with increased late onset AD risk (Laws et al., 2003; Serretti et al., 2007). Yet fewer than half of all AD sufferers possess the e4 allele and not all e4 carriers


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develop disease (Bertram, 2009). Thus, because APOE does not account for all the estimated heritability in LOAD, additional genes must be implicated together with environmental factors. Linkage studies have identified several promising chromosomal regions to harbor additional AD genes, including chromosomes 12, 10, 9 and 6 (Kamboh, 2004). A broad linkage peak encompassing a >60 cM region between chromosome 10q21 and 10q25 that influences both AD risk and age at onset has been suggested (Bertram et al., 2000; ErtekinTaner et al., 2000; Li et al., 2002; Myers et al., 2002). There are more than 300 genes in this broad genomic region of chromosome 10 and thus the task of identifying the candidate gene is daunting. One approach is to focus on known biological candidate genes in the region. There are a number of promising candidate genes in this region that are involved either in the production, processing, or clearance of b-amyloid peptide and among these is the choline O-acetyltransferase (CHAT) gene (gene accession number NM_020549, X56585 partial). CHAT-protein forms an integral part of the cholinergic system where it is responsible for catalyzing the synthesis of acetylcholine. Within the CNS, CHAT is synthesized in the perikaryon of cholinergic neurons, and transported to nerve terminals where it exists in soluble and membrane bound forms (Oda, 1999). By modulating levels of acetylcholine, CHAT influences a wide range of cholinergic-dependent neurophysiological functions including cognitive performance, arousal, sleep, movement, and the processing of visual information (Bacciottini et al., 2001; Beelke and Sannita, 2002; Selden et al., 1998). Although there is a widespread decline in various neurotransmitter-containing cell bodies in end-stage AD, the most consistent losses throughout the progression of AD are seen in long projection neurons, including cholinergic neurons of the basal forebrain (Auld et al., 2002; Mufson et al., 2003). Cholinergic neurons within the nucleus basalis and the septal diagonal band complex provide the major source of cholinergic innervation to the cerebral cortex and hippocampus, respectively, and play a key role in memory and attentional function (Auld et al., 2002; Mufson et al., 2003). Cholinergic basal forebrain cortical projection neurons contain the pathological AD hallmark, NFTs, and undergo chemical phenotypic alterations during the progression of AD (Mufson et al., 2007). Previously, some groups have examined the role of CHAT genetic variation with AD risk or age at onset, but the results have been equivocal (Ahn Jo et al., 2006; Cook et al., 2005; Harold et al., 2003; Kim et al., 2004; Mubumbila et al., 2002; Ozturk et al., 2006; Piccardi et al., 2007; Scacchi et al., 2009; Schwarz et al., 2003; Tang et al., 2008). Several studies examined multiple SNPs in the CHAT gene (Ahn Jo et al., 2006; Cook et al., 2005; Harold et al., 2003; Ozturk et al., 2006; Piccardi et al., 2007; Scacchi et al., 2009), while other studies examined only one SNP in exon 5, A120T (rs3810950) (Kim et al., 2004; Mubumbila et al., 2002; Schwarz et al., 2003), and most of these studies used relatively small sample sizes and thus fall short of providing conclusive results. The objective of this study was to use a broadly characterized longitudinal cohort study and an additional case-control study to examine the role of nineteen CHAT SNPs that previously showed suggestive associations with AD risk and quantitative trait of AD. As second aim, we examined the association of these SNPs to depression, since depression seems to intersect with AD (Grünblatt et al., 2008; Naarding et al., 2002), therefore one should examine any effects coming from depression rather than AD. 2. Methods 2.1. Patient recruitment and evaluation The present study investigated two samples described earlier in detail, namely the VITA study cohort (Fischer et al., 2008; Grünblatt

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et al., 2008) and the case-control Milano sample. Briefly, the VITA study is a prospective community-based cohort study in which all subjects were 75.76 0.45 years old at baseline recruitment coming from the geographical area of Vienna’s districts 21 and 22. Six hundred and six volunteers consented to participate in this study at basline. The Milano sample comprises 354 subjects originating from Northern Italy including two hundred and ten patients with AD (probable AD) consecutively recruited at the Alzheimer Unit of Ospedale Maggiore Policlinico (Milan). All patients underwent a standard battery of examinations, including medical history, physical and neurological examination, screening laboratory tests, neurocognitive evaluation, brain Magnetic Resonance Imaging (MRI) or Computed Tomography (CT) and, if indicated, Positron Emission Computed Tomography (PET). Dementia severity was assessed by the Clinical Dementia Rating (CDR) and the Mini Mental Scale Examination (MMSE). 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