title: Association of rs1006737 in CACNA1C with alterations in prefrontal activation and fronto-hippocampal connectivity.
abstract: BACKGROUND
  Genome-wide association studies have identified the rs1006737 single nucleotide polymorphism (SNP) in the CACNA1C gene as a susceptibility locus for schizophrenia and bipolar disorder. On the neural systems level this association is explained by altered functioning of the dorsolateral prefrontal cortex (DLPFC) and the hippocampal formation (HF), brain regions also affected by mental illness. In the present study we investigated the association of rs1006737 genotype with prefrontal activation and fronto-hippocampal connectivity.
  
  
  METHODS
  We used functional magnetic resonance imaging to measure neural activation during an n-back working memory task in 94 healthy subjects. All subjects were genotyped for the SNP rs1006737. We tested associations of the rs1006737 genotype with changes in working-memory-related DLPFC activation and functional integration using a seed region functional connectivity approach.
  
  
  RESULTS
  Rs1006737 genotype was associated with altered right-hemispheric DLPFC activation. The homozygous A (risk) group showed decreased activation compared to G-allele carriers. Further, the functional connectivity analysis revealed a positive association of fronto-hippocampal connectivity with rs1006737 A alleles.
  
  
  CONCLUSIONS
  We did not replicate the previous findings of increased right DLPFC activation in CACNA1C rs1006737 A homozygotes. In fact, we found the opposite effect, thus questioning prefrontal inefficiency as rs1006737 genotype-related intermediate phenotype. On the other hand, our results indicate that alterations in the functional coupling between the prefrontal cortex and the medial temporal lobe could represent a neural system phenotype that is mediated by CACNA1C rs1006737 and other genetic susceptibility loci for schizophrenia and bipolar disorder.
authors: Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Germany.
authors: Frieder M
authors: FM
authors: Paulus
authors: Johannes
authors: J
authors: Bedenbender
authors: Sören
authors: S
authors: Krach
authors: Martin
authors: M
authors: Pyka
authors: Axel
authors: A
authors: Krug
authors: Jens
authors: J
authors: Sommer
authors: Miriam
authors: M
authors: Mette
authors: Markus M
authors: MM
authors: Nöthen
authors: Stephanie H
authors: SH
authors: Witt
authors: Marcella
authors: M
authors: Rietschel
authors: Tilo
authors: T
authors: Kircher
authors: Andreas
authors: A
authors: Jansen
mesh_terms: D000483:Alleles; D001714:Bipolar Disorder / Q000235:genetics; D001931:Brain Mapping; D020746:Calcium Channels, L-Type / Q000235:genetics*; D005260:Female; D005625:Frontal Lobe / Q000502:physiology*; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006579:Heterozygote; D006624:Hippocampus / Q000502:physiology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology*; D009434:Neural Pathways / Q000502:physiology; D009483:Neuropsychological Tests; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017397:Prefrontal Cortex / Q000502:physiology*; D012559:Schizophrenia / Q000235:genetics; D013647:Task Performance and Analysis; D055815:Young Adult
chemical_list: C079146:CACNA1C protein, human; D020746:Calcium Channels, L-Type
keywords: CACNA1C; prefrontal connectivity; rs1006737; schizophrenia; working memory
references: Trends Genet. 2004 Sep;20(9):439-44
references: 15313553
references: Biol Psychiatry. 2008 May 1;63(9):852-7
references: 17949693
references: Arch Gen Psychiatry. 2011 Dec;68(12):1207-17
references: 21810628
references: Mol Psychiatry. 2008 Jun;13(6):558-69
references: 18317468
references: Neuroimage. 2003 Jul;19(3):751-63
references: 12880804
references: Mol Psychiatry. 2010 Feb;15(2):119-21
references: 20098439
references: J Affect Disord. 2009 Jul;116(1-2):70-9
references: 19117610
references: Hum Brain Mapp. 2009 Jul;30(7):1938-46
references: 19294651
references: PLoS One. 2011;6(12):e26354
references: 22220190
references: Psychol Med. 2011 Jul;41(7):1551-61
references: 21078228
references: J Neurosci. 2005 Oct 26;25(43):9883-92
references: 16251435
references: Hum Brain Mapp. 2005 May;25(1):60-9
references: 15846819
references: Arch Gen Psychiatry. 2009 Aug;66(8):811-22
references: 19652121
references: Neuropsychopharmacology. 2012 Feb;37(3):677-84
references: 22012475
references: Am J Psychiatry. 2003 Apr;160(4):709-19
references: 12668360
references: Nat Rev Neurosci. 2002 Mar;3(3):243-9
references: 11994756
references: Nature. 2010 Nov 11;468(7321):194-202
references: 21068827
references: Neuroimage. 2009 Apr 15;45(3):1002-8
references: 19167508
references: Hum Brain Mapp. 2013 Feb;34(2):304-13
references: 22042765
references: Hum Brain Mapp. 2010 Feb;31(2):266-75
references: 19650139
references: Trends Genet. 2009 Feb;25(2):99-105
references: 19144440
references: Am J Med Genet B Neuropsychiatr Genet. 2007 Jun 5;144B(4):407-16
references: 17440937
references: Neuroimage. 2010 Jan 15;49(2):1831-6
references: 19781653
references: Mol Psychiatry. 2010 Oct;15(10):1016-22
references: 19621016
references: Neurobiol Learn Mem. 2004 Mar;81(2):105-14
references: 14990230
references: Arch Gen Psychiatry. 2005 Apr;62(4):379-86
references: 15809405
references: Pharmacol Ther. 2005 Jun;106(3):347-55
references: 15922017
references: Cereb Cortex. 1999 Jan-Feb;9(1):20-6
references: 10022492
references: Curr Biol. 2011 Nov 22;21(22):1900-5
references: 22055295
references: Biol Psychiatry. 2003 Dec 15;54(12):1376-81
references: 14675801
references: Biol Psychiatry. 2010 Sep 15;68(6):586-8
references: 20638048
references: Schizophr Bull. 2009 May;35(3):509-27
references: 19155345
references: Br J Psychiatry. 1999 Sep;175:246-51
references: 10645326
references: Biol Psychiatry. 2006 Dec 1;60(11):1250-8
references: 16950222
references: Psychol Med. 2008 Jun;38(6):771-85
references: 17922938
references: Biol Psychiatry. 2003 Apr 1;53(7):624-6
references: 12679242
references: Am J Psychiatry. 2009 Dec;166(12):1413-4
references: 19952088
references: Mol Psychiatry. 2010 Sep;15(9):918-27
references: 19417742
references: Neuroimage. 2011 Feb 1;54(3):2514-23
references: 20946959
references: Schizophr Res. 2003 Apr 1;60(2-3):285-98
references: 12591590
references: Arch Gen Psychiatry. 2010 Aug;67(8):803-11
references: 20679588
references: J Psychiatr Res. 2005 Jul;39(4):391-8
references: 15804389
references: Arch Gen Psychiatry. 2010 Sep;67(9):939-45
references: 20819988
references: Am J Hum Genet. 2005 May;76(5):887-93
references: 15789306
references: Neuroimage. 2012 Oct 1;62(4):2250-60
references: 22100419
references: Eur Arch Psychiatry Clin Neurosci. 2011 Nov;261 Suppl 2:S150-4
references: 21866371
references: Neurosci Biobehav Rev. 2012 Jan;36(1):556-71
references: 21946175
references: Philos Trans R Soc Lond B Biol Sci. 1998 Nov 29;353(1377):1819-28
references: 9854254
references: Nature. 2007 Jun 7;447(7145):661-78
references: 17554300
references: Schizophr Res. 2007 Sep;95(1-3):70-5
references: 17628433
references: Am J Psychiatry. 2003 Oct;160(10):1809-16
references: 14514495
references: Neuroreport. 2003 Dec 2;14(17):2233-7
references: 14625454
references: Neuropsychologia. 1971 Mar;9(1):97-113
references: 5146491
references: Acta Psychiatr Scand. 2001 Mar;103(3):181-8
references: 11240574
references: Psychol Bull. 1971 Jun;75(6):424-9
references: 5580548
references: Biol Psychiatry. 2000 Oct 1;48(7):674-84
references: 11032979
references: Learn Mem. 2008 Jan 03;15(1):1-5
references: 18174367
references: Science. 2009 May 1;324(5927):605
references: 19407193
references: Eur Psychiatry. 2011 Apr;26(3):135-7
references: 21292451
references: Bipolar Disord. 2011 Nov-Dec;13(7-8):696-700
references: 22085483
references: Neurosci Biobehav Rev. 2011 Apr;35(5):1110-24
references: 21115039
references: Nat Genet. 2008 Sep;40(9):1056-8
references: 18711365