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      FAAH genetic variation enhances fronto-amygdala function in mouse and human

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          Abstract

          Cross-species studies enable rapid translational discovery and produce the broadest impact when both mechanism and phenotype are consistent across organisms. We developed a knock-in mouse that biologically recapitulates a common human mutation in the gene for fatty acid amide hydrolase (FAAH) (C385A; rs324420), the primary catabolic enzyme for the endocannabinoid anandamide. This common polymorphism impacts the expression and activity of FAAH, thereby increasing anandamide levels. Here, we show that the genetic knock-in mouse and human variant allele carriers exhibit parallel alterations in biochemisty, neurocircuitry, and behavior. Specifically, there is reduced FAAH expression associated with the variant allele that selectively enhances fronto-amygdala connectivity and fear extinction learning, and decreases anxiety-like behaviors. These results suggest a gain-of-function in fear regulation and may indicate for whom and for what anxiety symptoms FAAH inhibitors or exposure-based therapies will be most efficacious, bridging an important translational gap between the mouse and human.

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          Most cited references 57

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          Is Open Access

          An integrated map of genetic variation from 1,092 human genomes

          Summary Through characterising the geographic and functional spectrum of human genetic variation, the 1000 Genomes Project aims to build a resource to help understand the genetic contribution to disease. We describe the genomes of 1,092 individuals from 14 populations, constructed using a combination of low-coverage whole-genome and exome sequencing. By developing methodologies to integrate information across multiple algorithms and diverse data sources we provide a validated haplotype map of 38 million SNPs, 1.4 million indels and over 14 thousand larger deletions. We show that individuals from different populations carry different profiles of rare and common variants and that low-frequency variants show substantial geographic differentiation, which is further increased by the action of purifying selection. We show that evolutionary conservation and coding consequence are key determinants of the strength of purifying selection, that rare-variant load varies substantially across biological pathways and that each individual harbours hundreds of rare non-coding variants at conserved sites, such as transcription-factor-motif disrupting changes. This resource, which captures up to 98% of accessible SNPs at a frequency of 1% in populations of medical genetics focus, enables analysis of common and low-frequency variants in individuals from diverse, including admixed, populations.
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            AFNI: software for analysis and visualization of functional magnetic resonance neuroimages.

             C. R. Cox (1996)
            A package of computer programs for analysis and visualization of three-dimensional human brain functional magnetic resonance imaging (FMRI) results is described. The software can color overlay neural activation maps onto higher resolution anatomical scans. Slices in each cardinal plane can be viewed simultaneously. Manual placement of markers on anatomical landmarks allows transformation of anatomical and functional scans into stereotaxic (Talairach-Tournoux) coordinates. The techniques for automatically generating transformed functional data sets from manually labeled anatomical data sets are described. Facilities are provided for several types of statistical analyses of multiple 3D functional data sets. The programs are written in ANSI C and Motif 1.2 to run on Unix workstations.
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              R: A language and environment for statistical computing

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                Author and article information

                Journal
                101528555
                37539
                Nat Commun
                Nat Commun
                Nature communications
                2041-1723
                25 February 2015
                03 March 2015
                2015
                03 September 2015
                : 6
                : 6395
                Affiliations
                [1 ]Department of Psychiatry, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA
                [2 ]Department of Pharmacology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA
                [3 ]Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA
                [4 ]The Hotchkiss Brain Institute, Departments of Cell Biology and Anatomy & Psychiatry, University of Calgary, 3330 Hospital Drive NW, Calgary, AB Canada T2N4N1
                [5 ]inGenious Targeting Laboratory, 2200 Smithtown Avenue, Ronkonkoma, NY 11779, USA
                [6 ]Department of Chemical Physiology, The Scripps Research Institute, 10550N. Torrey Pines Rd., La Jolla, CA 92037, United States
                Author notes
                []Correspondence and requests for materials should be addressed to B.J.C. ( bjc2002@ 123456med.cornell.edu ) or F.S.L. ( fslee@ 123456med.cornell.edu )
                [*]

                These authors contributed equally to this work.

                Article
                NIHMS658410
                10.1038/ncomms7395
                4351757
                25731744

                Reprints and permissions information is available at www.nature.com/reprints.

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