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Genetic Variation Infgf20modulates Hippocampal Biology

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Genetic Variation Infgf20modulates Hippocampal Biology 5992 • The Journal of Neuroscience, April 28, 2010 • 30(17):5992–5997 Behavioral/Systems/Cognitive Genetic Variation in FGF20 Modulates Hippocampal Biology Herve Lemaitre,1 Venkata S. Mattay,1 Fabio Sambataro,1 Beth Verchinski,1 Richard E. Straub,1 Joseph H. Callicott,1 Raja Kittappa,2 Thomas M. Hyde,1 Barbara K. Lipska,1 Joel E. Kleinman,1 Ronald McKay,2 and Daniel R. Weinberger1 1Clinical Brain Disorder Branch, Genes, Cognition, and Psychosis Program, National Institutes of Health–National Institute of Mental Health, and 2Laboratory of Molecular Biology, National Institutes of Health–National Institute of Neurological Disorders and Stroke, Bethesda, Maryland 20892 Weexploredtheeffectofsingle-nucleotidepolymorphisms(SNPs)inthefibroblastgrowthfactor20gene(FGF20)associatedwithriskfor Parkinson’s disease on brain structure and function in a large sample of healthy young-adult human subjects and also in elderly subjects to look at the interaction between genetic variations and age (N ϭ 237; 116 men; 18–87 years). We analyzed high-resolution anatomical magnetic resonance images using voxel-based morphometry, a quantitative neuroanatomical technique. We also measured FGF20 mRNA expression in postmortem human brain tissue to determine the molecular correlates of these SNPs (N ϭ 108; 72 men; 18–74 years). We found that the T allele carriers of rs12720208 in the 3Ј-untranslated region had relatively larger hippocampal volume ( p ϭ 0.0059) and diminished verbal episodic memory ( p ϭ 0.048) and showed steeper decreases of hippocampal volume with normal aging ( p ϭ 0.026). In postmortem brain, T allele carriers had greater expression of hippocampal FGF20 mRNA ( p ϭ 0.037), consistent with a previously characterized microRNA mechanism. The C allele matches a predicted miR-433 microRNA binding domain, whereas the T allele disrupts it, resulting in higher FGF20 protein translation. The strong FGF20 genetic effects in hippocampus are presumably mediated by activation of the FGFR1 (FGF receptor 1), which is expressed in mammalian brain most abundantly in the hippocampus. These associations, from mRNA expression to brain morphology to cognition and an interaction with aging, confirm a role of FGF20 in human brain structure and function during development and aging. Introduction In a family-based genetic study, van der Walt et al. (2004) re- The abundant expression of fibroblast growth factor 20 (FGF20) ported association of FGF20 single-nucleotide polymorphisms in the midbrain, its role in dopaminergic (DA) neuron survival, (SNPs) with increased risk for PD. Two SNPs located in the 3Ј- and its location on chromosome 8 p22-p21.3 close to a Parkin- untranslated region (UTR) of the gene, rs12720208[C/T] (T allele son’s disease (PD) linkage peak (Scott et al., 2001), have made positively associated; p ϭ 0.0008) and rs1721100[C/G] (C allele pos- FGF20 a promising candidate gene for PD. As a neurotrophin, itively associated; p ϭ 0.02), and one intronic SNP, rs1989754[C/G] FGF20 plays critical roles not only in the growth and survival of (C allele positively associated; p ϭ 0.0006), showed association with neurons in early development but also in the biology of adult illness (see Fig. 1). One of these SNPs, rs12720208, was subsequently neurons. FGF20 appears to be specifically expressed within the shown in tissue culture to affect the translation of FGF20 via disrupt- brain and particularly within neurons of the substantia nigra ing a putative microRNA binding site within the 3Ј-untranslated (Ohmachi et al., 2000) and cerebellum (Jeffers et al., 2001). region (Wang et al., 2008). Specifically, the risk-associated allele in FGF20 mediates its biological response by activating a cell FGF20 removed this binding domain and resulted in relatively surface tyrosine kinase FGF receptor-1 (FGFR1) (Ohmachi et al., greater levels of FGF20 protein and presumably greater FGF20 2003). FGF20 signaling has been studied in DA neurons of the effects. substantia nigra, as a potential factor related to the pathogenesis The evidence from functional data of the role of a SNP in and potential treatment of Parkinson’s disease, where it pro- regulating expression of FGF20 makes examination of the effect motes the survival of calbindin-negative DA neurons that express of FGF20 SNPs on brain structure and function of considerable specifically FGFR1 (Murase and McKay, 2006). FGFR1 expression interest. We explored in this study the impact of these risk- also is widely distributed in the brain from neocortex to amygdala, associated genetic polymorphisms (rs12720208, rs1721100, and caudate nucleus, substantia nigra, thalamus, and hippocampus rs1989754) on the morphology of the brain in a large sample of (Weickert et al., 2005), the latter structure expressing the highest healthy young adult using voxel-based morphometry (VBM), a level of FGFR1 in brain (Takami et al., 1998; Fu et al., 2003). quantitative neuroanatomical magnetic resonance imaging (MRI) technique (Good et al., 2001). A sample of elderly subjects was also included to study specifically the interaction between age Received Nov. 19, 2009; revised Jan. 27, 2010; accepted March 9, 2010. This work was supported by the Intramural Research Program of the National Institute of Mental Health– and genetic variation. We also measured FGF20 mRNA expres- National Institutes of Health. sion in postmortem human brain tissue to determine the molec- Correspondence should be addressed to Dr. Daniel R. Weinberger, Genes, Cognition, and Psychosis Program, ular correlates of these SNPs. We hypothesized that genetic Division of Intramural Research Programs, National Institutes of Health–National Institute of Mental Health, 10 variations associated with increased risk for PD and modulation Center Drive, MSC 1379, Bethesda, MD 20892. E-mail: [email protected]. DOI:10.1523/JNEUROSCI.5773-09.2010 of gene expression should have a direct or indirect effect on mea- Copyright © 2010 the authors 0270-6474/10/305992-06$15.00/0 sures of brain structures and also on related cognitive functions. Lemaitre et al. • Genetic Variation in FGF20 Modulates Hippocampal Biology J. Neurosci., April 28, 2010 • 30(17):5992–5997 • 5993 medium regularization, 16 nonlinear itera- tions) to a representative GM template derived from a subset of 140 subjects (70 men) statisti- cally similar for age, intelligence quotient (IQ), and education level with the entire study group. The GM warping parameters so ob- tained were then used to spatially normalize the whole-brain T1 volume, the resulting vol- ume being further interpolated as 1 mm 3 iso- tropic voxel. Then, the normalized whole- brain T1 volume was segmented using a priori Figure1. GenestructureofFGF20(9.341kb)onchromosome8p22.ThecodingregionsandtheUTRsareindicatedbytheclosed GM, white matter (WM), and CSF probability and open boxes, respectively. rs11203822 (a surrogate for rs1989754) (see Materials and Methods) is in the first intron, and maps derived from the subset of subjects pre- rs1721100 and rs12720208 (a surrogate for rs17514985) (see Results) are in the 3Ј-UTR regulatory region. viously described. Then, a so-called “modula- tion” step was added, to adjust voxel intensity for the strength of the deformation performed Materials and Methods during the spatial normalization process. This step was applied to each Subjects. The study sample consisted of 237 normal volunteers, including tissue partition to preserve the subject’s original tissue quantity after its 194 healthy volunteers (18–58 years of age) recruited as part of the Clin- transfer to the reference space. Finally, all tissue images were smoothed ical Brain Disorders Branch Sibling Study [National Institutes of Health with a 10 mm full-width half-maximum Gaussian kernel. For each sub- (NIH) Study ID NCT00001486] described in detail previously (Egan et ject, GM, WM, and CSF volumes were computed as the integral of the al., 2001) and an additional 43 healthy volunteers (60–87 years of age) voxel intensities of the corresponding modulated tissue image. Total recruited as part of a study of normal aging (NIH Study ID intracranial volume was defined as the sum of the GM, WM, and CSF NCT0001284). The elderly subjects were included in the study to answer volumes. To estimate the magnitude of the genetic effect, we estimated the question of the interaction between genetic variation and age. To the hippocampal volume by calculating the integral of the voxel intensi- reduce genetic heterogeneity, we included only Caucasian subjects of ties within the hippocampal region (Lemaitre et al., 2005). The hip- European ancestry who were free of any history of psychiatric or neuro- pocampal boundary was automatically derived from an independent logical illness, of psychiatric treatment, or of drug or alcohol abuse within model of macroscopic neuroanatomical parcellation (automated ana- the 12 months before participation in this study. All of the subjects gave tomical labeling) (Tzourio-Mazoyer et al., 2002). written informed consent and participated in the study according to the Imaging statistics. Because of the low minor allele frequencies of guidelines of the National Institute of Mental Health Institutional Re- rs12720208 and rs1721100, few subjects were T/T and G/G, respectively view Board. (Ͻ7% of the sample). For this reason, we combined minor allele het- DNA collection and genotyping. DNA was extracted from whole blood erozygotes and homozygotes for these two SNPs. Consequently, single using standard procedures. All genotypes were determined using
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