Genetic variation in catechol-O-methyltransferase: effects on working memory in schizophrenic patients, their siblings, and healthy controls.
BACKGROUND
Catechol-O-methyltransferase (COMT) val(108/158)met (rs4680) is thought to affect dopamine regulated prefrontal cortical activity during working memory (WM) tasks, and to weakly increase risk for developing schizophrenia. Recently, other single nucleotide polymorphisms (SNPs) across the gene have emerged as additional risk factors for schizophrenia: namely rs737865, rs165599, and rs2097603. In a large sample, we examined whether these SNPs affect WM.


METHODS
Schizophrenic probands (n = 325), their nonpsychotic siblings (n = 359), and normal control subjects (n = 330) completed tests of WM function. Data were analyzed with a series of mixed model analyses of variance (ANOVAs).


RESULTS
Val homozygotes performed most poorly on all conditions of the n-back, irrespective of diagnosis. Additionally, there was a trend towards a disease-only val(108/158)met effect on a test of attentional set-shifting; val homozygote probands performed most poorly. Significant or near-significant effects of rs737865 were found on all conditions of the n-back, with G homozygotes performing worst. There also was a disease-only COMT rs737865 effect on the 0-back. None of the other SNPs showed main effects by themselves. A haplotype constructed from promoter and val(108/158)met SNPs showed main effects on WM parameters, consistent with inverted U models of dopamine signaling.


CONCLUSIONS
We extended earlier findings of a val(108/158)met effect on WM function, and suggest that combinations of alleles within COMT may modulate the val(108/158)met effect in a nonlinear manner.
Diaz-Asper
Catherine M
CM
Clinical Brain Disorders Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA.
Goldberg
Terry E
TE
Kolachana
Bhaskar S
BS
Straub
Richard E
RE
Egan
Michael F
MF
Weinberger
Daniel R
DR
D000328:Adult; D016022:Case-Control Studies; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D005192:Family Health; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology*; D008715:Methionine / Q000235:genetics; D008875:Middle Aged; D009483:Neuropsychological Tests; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology*; D014633:Valine / Q000235:genetics
D008715:Methionine; D002394:Catechol O-Methyltransferase; D014633:Valine
Biol Psychiatry. 2005 Jan 15;57(2):139-44
15652872
Mol Psychiatry. 2005 Mar;10(3):229, 287-98
15668720
Nat Neurosci. 2005 May;8(5):594-6
15821730
J Neurosci. 2005 May 18;25(20):5038-45
15901785
J Int Neuropsychol Soc. 2005 Mar;11(2):202-4
15962707
Mol Psychiatry. 2006 May;11(5):446-58
16505837
Biol Psychiatry. 2006 Jul 15;60(2):141-51
16476412
Mol Psychiatry. 2006 Sep;11(9):867-77, 797
16786032
Schizophr Res. 2007 Jan;89(1-3):339-49
17055703
Neuropsychopharmacology. 2007 May;32(5):1011-20
17063156
Hum Genet. 2002 Dec;111(6):521-37
12436243
Am J Hum Genet. 2002 Dec;71(6):1296-302
12402217
Neurosci Lett. 2003 Feb 27;338(2):123-6
12566168
Am J Psychiatry. 2000 Jan;157(1):26-33
10618009
Mol Psychiatry. 2000 Jan;5(1):77-84
10673772
Am J Psychiatry. 2000 Aug;157(8):1309-16
10910796
Arch Gen Psychiatry. 2000 Sep;57(9):907-13
10986554
Cereb Cortex. 2000 Nov;10(11):1078-92
11053229
Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6917-22
11381111
Cereb Cortex. 2001 Nov;11(11):1015-26
11590111
Biol Psychiatry. 2001 Dec 1;50(11):825-44
11743939
Am J Psychiatry. 2002 Apr;159(4):652-4
11925305
Arch Gen Psychiatry. 2002 Jul;59(7):662-3
12090821
Prog Neurobiol. 2002 May;67(1):53-83
12126656
Biol Psychiatry. 2002 Oct 1;52(7):701-7
12372660
Am J Hum Genet. 2003 Jul;73(1):152-61
12802784
Am J Psychiatry. 2003 Mar;160(3):469-76
12611827
Proc Natl Acad Sci U S A. 2003 May 13;100(10):6186-91
12716966
Biol Psychiatry. 1999 Aug 15;46(4):557-67
10459407
Am J Med Genet. 1999 Oct 15;88(5):497-502
10490706
Mol Psychiatry. 2005 Jan;10(1):40-68; image 5
15263907
Am J Med Genet B Neuropsychiatr Genet. 2003 Jul 1;120B(1):47-50
12815739
Biol Psychiatry. 2003 Jul 1;54(1):40-8
12842307
Arch Gen Psychiatry. 2003 Sep;60(9):889-96
12963670
Am J Psychiatry. 2004 Jun;161(6):1110-2
15169701
Psychopharmacology (Berl). 2004 Jun;174(1):86-98
15071717
Mol Psychiatry. 2004 Sep;9(9):859-70
15098000
Biol Psychiatry. 2004 Oct 1;56(7):510-5
15450787
Mol Psychiatry. 2004 Oct;9(10):962-7
15124004
Am J Hum Genet. 2004 Nov;75(5):807-21
15457404
Neuropsychopharmacology. 2004 Nov;29(11):1943-61
15305167
J R Soc Med. 1992 Jul;85(7):399-402
1629849
Psychiatr Genet. 1996 Fall;6(3):131-3
8902889
Adv Pharmacol. 1998;42:707-11
9327997
Biol Psychiatry. 1998 May 15;43(10):723-9
9606525
Neuroscience. 1999;92(4):1343-56
10426489