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Associations Between Variants Near a Monoaminergic Pathways Gene (PHOX2B) and Amygdala Reactivity: A Genome-Wide Functional Imaging Study

  • Olga Therese Ousdal (a1) (a2), Andrew Anand Brown (a1) (a2), Jimmy Jensen (a1) (a2) (a3), Per H. Nakstad (a4), Ingrid Melle (a1) (a2), Ingrid Agartz (a1) (a2), Srdjan Djurovic (a1) (a2), Ryan Bogdan (a5), Ahmad R. Hariri (a5) (a6) and Ole A. Andreassen (a1) (a2)...

As the amygdala is part of the phylogenetic old brain, and its anatomical and functional properties are conserved across species, it is reasonable to assume genetic influence on its activity. A large corpus of candidate gene studies indicate that individual differences in amygdala activity may be caused by genetic variants within monoaminergic signaling pathways such as dopamine, serotonin, and norepinephrine. However, to our knowledge, the use of genome-wide data to discover genetic variants underlying individual differences in adult amygdala activity is novel. In the present study, the combination of genome-wide data and functional imaging phenotypes from an emotional faces task yielded a significant association between rs10014254 and the amygdala using a region of interest approach. This single nucleotide polymorphism is located in a regulatory region upstream of the Paired-like homeobox 2b (PHOX2B) gene; therefore it could affect the expression of this gene. PHOX2B regulates the expression of enzymes necessary for the synthesis of several monoamines and is essential for the development of the autonomic nervous system. However, an attempt to replicate the finding in an independent sample from North America did not succeed. The synthesis of functional magnetic resonance imaging (fMRI) and genome-wide data takes a hypothesis-free approach as to which genetic variants are of interest. Therefore, we believe that an undirected finding within such a plausible region is of interest, and that our results add further support to the hypothesis that monoaminergic signaling pathways play a central role in regulating amygdala activity.

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Corresponding author
address for correspondence: Olga Therese Ousdal, MD, Psychosis Research Section (TOP), Building 49, Division of Mental Health and Addiction, Oslo University Hospital, Kirkeveien 166, N-0407 Oslo, Norway. E-mail:
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This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

D. G. Amaral (2003). The amygdala, social behavior, and danger detection. Annals of the New York Academy of Science, 1000, 337347.

N. A. Antic , B. A. Malow , N. Lange , R. D. McEvoy , A. L. Olson , P. Turkington , W. Windisch , M. Samuels , C. A. Stevens , E. M. Berry-Kravis , & D. E. Weese-Mayer (2006). PHOX2B mutation-confirmed congenital central hypoventilation syndrome: Presentation in adulthood. American Journal of Respiratory and Critical Care Medicine, 174, 923927.

B. W. Balleine , & S. Killcross (2006). Parallel incentive processing: An integrated view of amygdala function. Trends in Neuroscience, 29, 272279.

E. Birney , J. A. Stamatoyannopoulos , A. Dutta , R. Guigo , T. R. Gingeras , E. H. Margulies , & P. J. de Jong (2007). Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature, 447, 799816.

J. F. Brunet , & A. Pattyn (2002). Phox2 genes — from patterning to connectivity. Current Opinion in Genetics and Development, 12, 435440.

D. M. Buffalari , & A. A. Grace (2007). Noradrenergic modulation of basolateral amygdala neuronal activity: Opposing influences of alpha-2 and beta receptor activation. Journal of Neuroscience, 27, 1235812366.

N. S. Burghardt , D. E. Bush , B. S. McEwen , & J. E. LeDoux (2007). Acute selective serotonin reuptake inhibitors increase conditioned fear expression: Blockade with a 5-HT(2C) receptor antagonist. Biological Psychiatry, 62, 11111118.

J. M. Carre , P. M. Fisher , S. B. Manuck , & A. R. Hariri (2010). Interaction between trait anxiety and trait anger predict amygdala reactivity to angry facial expressions in men but not women. Social Cognitive and Affective Neuroscience, 7, 213221.

A. Caspi , J. McClay , T. E. Moffitt , J. Mill , J. Martin , I. W. Craig , A. Taylor , & R. Poulton (2002). Role of genotype in the cycle of violence in maltreated children. Science, 297, 851854.

S. J. Chanock , T. Manolio , M. Boehnke , E. Boerwinkle , D. J. Hunter , G. Thomas , J. N. Hirschhorn , G. Abecasis , D. Altshuler , J. E. Bailey-Wilson , L. D. Brooks , L. R. Cardon , M. Daly , P. Donnelly , J. F., Jr. Fraumeni , N. B. Freimer , D. S. Gerhard , C. Gunter , A. E. Guttmacher , M. S. Guyer , E. L. Harris , J. Hoh , R. Hoover , C. A. Kong , K. R. Merikangas , C. C. Morton , L. J. Palmer , E. G. Phimister , J. P. Rice , J. Roberts , C. Rotimi , M. A. Tucker , K. J. Vogan , S. Wacholder , E. M. Wijsman , D. M. Winn , & F. S. Collins (2007). Replicating genotype-phenotype associations. Nature, 447, 655660.

M. Davis (1992). The role of the amygdala in fear-potentiated startle: Implications for animal models of anxiety. Trends in Pharmacological Science, 13, 3541.

M. Davis , & P. J. Whalen (2001). The amygdala: Vigilance and emotion. Molecular Psychiatry, 6, 1334.

A. Etkin , K. C. Klemenhagen , J. T. Dudman , M. T. Rogan , R. Hen , E. R. Kandel , & J. Hirsch (2004). Individual differences in trait anxiety predict the response of the basolateral amygdala to unconsciously processed fearful faces. Neuron, 44, 10431055.

K. J. Friston , A. P. Holmes , J. B. Poline , P. J. Grasby , S. C. Williams , R. S. Frackowiak , & R. Turner (1995). Analysis of fMRI time-series revisited. Neuroimage, 2, 4553.

C. Gross , & R. Hen (2004). The developmental origins of anxiety. Nature Reviews Neuroscience, 5, 545552.

A. R. Hariri (2009). The neurobiology of individual differences in complex behavioral traits. Annual Review of Neuroscience, 32, 225247.

A. R. Hariri , E. M. Drabant , K. E. Munoz , B. S. Kolachana , V. S. Mattay , M. F. Egan , & D. R. Weinberger (2005). A susceptibility gene for affective disorders and the response of the human amygdala. Archives of General Psychiatry, 62, 146152.

A. R. Hariri , V. S. Mattay , A. Tessitore , B. Kolachana , F. Fera , D. Goldman , M. F. Egan , & D. R. Weinberger (2002). Serotonin transporter genetic variation and the response of the human amygdala. Science, 297, 400403.

H. E. Hulshoff Pol , H. G. Schnack , D. Posthuma , R. C. Mandl , W. F. Baare , C. van Oel , N. E. van Haren , D. L. Collins , A. C. Evans , K. Amunts , U. Burgel , K. Zilles , E. de Geus , D. I. Boomsma , & R. S. Kahn (2006). Genetic contributions to human brain morphology and intelligence. Journal of Neuroscience, 26, 1023510242.

, & (). . , , –. R. Ihaka R. Gentleman 1996 R: A Language for data analysis and graphics Journal of Computational and Graphical Statistics 5 299314

The International HapMap Project. (2003). Nature, 426, 789796.

J. Jacob , A. L. Ferri , C. Milton , F. Prin , P. Pla , W. Lin , A. Gavalas , S. L. Ang , & J. Briscoe (2007). Transcriptional repression coordinates the temporal switch from motor to serotonergic neurogenesis. Nature Neuroscience, 10, 14331439.

A. D. Johnson , R. E. Handsaker , S. L. Pulit , M. M. Nizzari , C. J. O'Donnell , & P. I. de Bakker (2008). SNAP: A web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics, 24, 29382939.

B. S. Kapp , M. Gallagher , M. D. Underwood , C. L. McNall , & D. Whitehorn (1982). Cardiovascular responses elicited by electrical stimulation of the amygdala central nucleus in the rabbit. Brain Research, 234, 251262.

R. Kumar , P. M. Macey , M. A. Woo , J. R. Alger , & R. M. Harper (2006). Elevated mean diffusivity in widespread brain regions in congenital central hypoventilation syndrome. Journal of Magnetic Resonance Imaging, 24, 12521258.

R. Kumar , P. M. Macey , M. A. Woo , J. R. Alger , T. G. Keens , & R. M. Harper (2005). Neuroanatomic deficits in congenital central hypoventilation syndrome. Journal of Comparative Neurology, 487, 361371.

J. LeDoux (2003). The emotional brain, fear, and the amygdala. Cellular and Molecular Neurobiology, 23, 727738.

J. LeDoux (2007). The amygdala. Current Biology, 17, R868874.

E. S. Lein , M. J. Hawrylycz , N. Ao , M. Ayres , A. Bensinger , A. Bernard , . . . A. R. Jones (2007). Genome-wide atlas of gene expression in the adult mouse brain. Nature, 445, 168176.

X. Liu , N. Akula , M. Skup , M. A. Brotman , E. Leibenluft , & F. J. McMahon (2010). A genome-wide association study of amygdala activation in youths with and without bipolar disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 49, 3341.

J. A. Maldjian , P. J. Laurienti , & J. H. Burdette (2004). Precentral gyrus discrepancy in electronic versions of the Talairach atlas. Neuroimage, 21, 450455.

J. A. Maldjian , P. J. Laurienti , R. A. Kraft , & J. H. Burdette (2003). An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. Neuroimage, 19, 12331239.

S. B. Manuck , S. M. Brown , E. E. Forbes , & A. R. Hariri (2007). Temporal stability of individual differences in amygdala reactivity. American Journal of Psychiatry, 164, 16131614.

A. Meyer-Lindenberg , J. W. Buckholtz , B. A. R. H. Kolachana , L. Pezawas , G. Blasi , A. Wabnitz , R. Honea , B. Verchinski , J. H. Callicott , M. Egan , V. Mattay , & D. R. Weinberger (2006). Neural mechanisms of genetic risk for impulsivity and violence in humans. Proceedings of the National Academy of Sciences USA, 103, 62696274.

R. W. Morris , C. S. Weickert , & C. M. Loughland (2009). Emotional face processing in schizophrenia. Current Opinion in Psychiatry, 22, 140146.

S. E. Morrison , & C. D. Salzman (2010). Re-valuing the amygdala. Current Opinion in Neurobiology, 20, 221230.

O. T. Ousdal , J. Jensen , A. Server , A. R. Hariri , P. H. Nakstad , & O. A. Andreassen (2008). The human amygdala is involved in general behavioral relevance detection: Evidence from an event-related functional magnetic resonance imaging Go-NoGo task. Neuroscience, 156, 450455.

P. P. Patwari , M. S. Carroll , C. M. Rand , R. Kumar , R. Harper , & D. E. Weese-Mayer (2010). Congenital central hypoventilation syndrome and the PHOX2B gene: A model of respiratory and autonomic dysregulation. Respiratory Physiology and Neurobiology, 173, 322335.

J. S. Peper , H. G. Schnack , R. M. Brouwer , G. C. van Baal , E. Pjetri , E. Szekely , M. van Leeuwen , S. M. van den Berg , D. L. Collins , A. C. Evans , D. I. Boomsma , R. S. Kahn , & H. E. Hulshoff Pol (2009). Heritability of regional and global brain structure at the onset of puberty: A magnetic resonance imaging study in 9-year-old twin pairs. Human Brain Mapping, 30, 21842196.

L. Pezawas , A. Meyer-Lindenberg , E. M. Drabant , B. A. Verchinski , K. E. Munoz , B. S. Kolachana , M. F. Egan , V. S. Mattay , A. R. Hariri , & D. R. Weinberger (2005). 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: A genetic susceptibility mechanism for depression. Nature Neuroscience, 8, 828834.

S. Purcell , B. Neale , K. Todd-Brown , L. Thomas , M. A. Ferreira , D. Bender , J. Maller , P. Sklar , P. I. de Bakker , M. J. Daly , & P. C. Sham (2007). PLINK: A tool set for whole-genome association and population-based linkage analyses. American Journal of Human Genetics, 81, 559575.

L. M. Rimol , I. Agartz , S. Djurovic , A. A. Brown , J. C. Roddey , A. K. Kahler , M. Mattingsdal , L. Athanasiu , A. H. Joyner , N. J. Schork , E. Halgren , K. Sundet , I. Melle , A. M. Dale , & O. A. Andreassen (2010). Sex-dependent association of common variants of microcephaly genes with brain structure. Proceedings of the National Academy of Sciences USA, 107, 384388.

H. Ruof , J. Hammer , B. Tillmann , D. Ghelfi , & P. Weber (2008). Neuropsychological, behavioral, and adaptive functioning of Swiss children with congenital central hypoventilation syndrome. Journal of Child Neurology, 23, 12541259.

D. Sander , J. Grafman , & T. Zalla (2003). The human amygdala: An evolved system for relevance detection. Reviews in the Neurosciences, 14, 303316.

K. Sergerie , C. Chochol , & J. L. Armony (2008). The role of the amygdala in emotional processing: A quantitative meta-analysis of functional neuroimaging studies. Neuroscience and Biobehavioral Reviews, 32, 811830.

L. M. Shin , S. P. Orr , M. A. Carson , S. L. Rauch , M. L. Macklin , N. B. Lasko , P. M. Peters , L. J. Metzger , D. D. Dougherty , P. A. Cannistraro , N. M. Alpert , A. J. Fischman , & R. K. Pitman (2004). Regional cerebral blood flow in the amygdala and medial prefrontal cortex during traumatic imagery in male and female Vietnam veterans with PTSD. Archives of General Psychiatry, 61, 168176.

M. N. Smolka , G. Schumann , J. Wrase , S. M. Grusser , H. Flor , K. Mann , D. F. Braus , D. Goldman , C. Buchel , & A. Heinz (2005). Catechol-O-methyltransferase val158met genotype affects processing of emotional stimuli in the amygdala and prefrontal cortex. Journal of Neuroscience, 25, 836842.

M. B. Stein , P. R. Goldin , J. Sareen , L. T. Zorrilla , & G. G. Brown (2002). Increased amygdala activation to angry and contemptuous faces in generalized social phobia. Archives of General Psychiatry, 59, 10271034.

A. Subramanian , P. Tamayo , V. K. Mootha , S. Mukherjee , B. L. Ebert , M. A. Gillette , A. Paulovich , S. L. Pomeroy , T. R. Golub , E. S. Lander , & J. P. Mesirov (2005). Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proceedings of the National Academy of Sciences USA, 102, 1554515550.

H. Takahashi , N. Yahata , M. Koeda , A. Takano , K. Asai , T. Suhara , & Y. Okubo (2005). Effects of dopaminergic and serotonergic manipulation on emotional processing: A pharmacological fMRI study. Neuroimage, 27, 9911001.

N. Tottenham , J. W. Tanaka , A. C. Leon , T. McCarry , M. Nurse , T. A. Hare , D. J. Marcus , A. Westerlund , B. J. Casey , & C. Nelson (2009). The NimStim set of facial expressions: Judgments from untrained research participants. Psychiatry Research, 168, 242249.

T. Toyota , K. Yoshitsugu , M. Ebihara , K. Yamada , H. Ohba , M. Fukasawa , Y. Minabe , K. Nakamura , Y. Sekine , N. Takei , K. Suzuki , M. Itokawa , J. M. Meerabux , Y. Iwayama-Shigeno , Y. Tomaru , H. Shimizu , E. Hattori , N. Mori , & T. Yoshikawa (2004). Association between schizophrenia with ocular misalignment and polyalanine length variation in PMX2B. Human Molecular Genetics, 13, 551561.

M. Vanderlaan , C. R. Holbrook , M. Wang , A. Tuell , & D. Gozal (2004). Epidemiologic survey of 196 patients with congenital central hypoventilation syndrome. Pediatric Pulmonology, 37, 217229.

A. H. van Stegeren , R. Goekoop , W. Everaerd , P. Scheltens , F. Barkhof , J. P. Kuijer , & S. A. Rombouts (2005). Noradrenaline mediates amygdala activation in men and women during encoding of emotional material. Neuroimage, 24, 898909.

R. Viviani (2010). Unbiased ROI selection in neuroimaging studies of individual differences. Neuroimage, 50, 184189.

D. H. Zald (2003). The human amygdala and the emotional evaluation of sensory stimuli. Brain Research Reviews, 41, 88123.

S. Zollner , & J. K. Pritchard (2007). Overcoming the winner's curse: Estimating penetrance parameters from case-control data. American Journal of Human Genetics, 80, 605615.

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