Genetic variation in FGF20 modulates hippocampal biology.
We explored the effect of single-nucleotide polymorphisms (SNPs) in the fibroblast growth factor 20 gene (FGF20) associated with risk for 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 = 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 = 108; 72 men; 18-74 years). We found that the T allele carriers of rs12720208 in the 3'-untranslated region had relatively larger hippocampal volume (p = 0.0059) and diminished verbal episodic memory (p = 0.048) and showed steeper decreases of hippocampal volume with normal aging (p = 0.026). In postmortem brain, T allele carriers had greater expression of hippocampal FGF20 mRNA (p = 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.
Lemaitre
Herve
H
Clinical Brain Disorder Branch, Genes, Cognition, and Psychosis Program, National Institutes of Health-National Institute of Mental Health, Bethesda, Maryland 20892, USA.
Mattay
Venkata S
VS
Sambataro
Fabio
F
Verchinski
Beth
B
Straub
Richard E
RE
Callicott
Joseph H
JH
Kittappa
Raja
R
Hyde
Thomas M
TM
Lipska
Barbara K
BK
Kleinman
Joel E
JE
McKay
Ronald
R
Weinberger
Daniel R
DR
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism* / Q000473:pathology*; D000483:Alleles; D003071:Cognition / Q000502:physiology; D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism*; D005838:Genotype; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000378:metabolism; D008875:Middle Aged; D009929:Organ Size; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D055815:Young Adult
C416003:FGF20 protein, human; C548883:MIRN433 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D005346:Fibroblast Growth Factors; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1