Association of serotonin and dopamine gene pathways with behavioral subphenotypes in dementia.
Genetic association studies investigating the association between genes of serotonergic and dopaminergic systems and behavioral and psychological symptoms in dementia (BPSD) are contradictory. We have utilized 1008 probable Alzheimer's disease (AD) patients from the UK and used the 12-item Neuropsychiatric Inventory. We applied a multiple indicators-multiple causes (MIMIC) approach to investigate the effect of 11 polymorphisms on the 4 behavioral subphenotypes "psychosis", "moods", "agitation", and "behavioural dyscontrol". Significant associations were observed between the serotonin transporter gene (SERT) polymorphism STin2 and "psychosis"; the dopamine transporter gene (DAT) 3' variable number tandem repeats (VNTR) and "agitation"; and the dopamine receptor 4 (DRD4) VNTR and "moods" factors. Direct associations were identified between the dopamine receptor 3 (DRD3) BalI polymorphism and depression; the dopamine receptor 1 (DRD1) and dopamine transporter gene 3' VNTR polymorphisms and aberrant motor behavior; the DRD4 VNTR and sleep disturbances; and the SERT gene VNTR 5HTTLPR and apathy items. Significant interactions observed between polymorphisms suggested epistatic effects and interactions between polymorphisms and medications highlighted potential treatment response. This multiple indicators multiple causes (MIMIC) model efficiently captured the complexity of the interrelations between genetic variation, behavioral symptoms, and clinical variables.
Proitsi
Petroula
P
Institute of Psychiatry, King's College London, London, UK. petroula.proitsi@kcl.ac.uk
Lupton
Michelle K
MK
Reeves
Suzanne J
SJ
Hamilton
Gillian
G
Archer
Nicola
N
Martin
Belinda M
BM
Iyegbe
Conrad
C
Hollingworth
Paul
P
Lawlor
Brian
B
Gill
Michael
M
Brayne
Carol
C
Rubinsztein
David C
DC
Owen
Michael J
MJ
Williams
Julie
J
Lovestone
Simon
S
Powell
John F
JF
D000368:Aged; D000369:Aged, 80 and over; D053327:Apolipoprotein E4 / Q000235:genetics; D001526:Behavioral Symptoms / Q000209:etiology / Q000235:genetics*; D002394:Catechol O-Methyltransferase / Q000235:genetics; D016009:Chi-Square Distribution; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D003704:Dementia / Q000150:complications / Q000235:genetics / Q000523:psychology; D004298:Dopamine / Q000235:genetics*; D050483:Dopamine Plasma Membrane Transport Proteins; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D018598:Minisatellite Repeats / Q000235:genetics; D008954:Models, Biological; D008995:Monoamine Oxidase / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D011569:Psychiatric Status Rating Scales; D011954:Receptors, Dopamine; D012307:Risk Factors; D012701:Serotonin / Q000235:genetics*; D050486:Serotonin Plasma Membrane Transport Proteins; D015398:Signal Transduction / Q000235:genetics*; D006113:United Kingdom
D053327:Apolipoprotein E4; D050483:Dopamine Plasma Membrane Transport Proteins; D011954:Receptors, Dopamine; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D008995:Monoamine Oxidase; D002394:Catechol O-Methyltransferase; D004298:Dopamine