A dopamine receptor D2 genetic polymorphism associated with transition to mental disorders in a cohort of individuals with at-risk mental state for psychosis

Marques, Julia Hatagami; Talib, Leda Leme; Hortêncio, Lucas; Andrade, Julio Cesar; Alves, Tania Maria; Serpa, Mauricio Henriques; Yamamoto, Guilherme Lopes; van de Bilt, Martinus Theodorus; Rössler, Wulf; Gattaz, Wagner Farid; Loch, Alexandre Andrade

doi:10.47626/1516-4446-2023-3044

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Brazilian Journal of Psychiatry

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BRIEF COMMUNICATION • Braz J Psychiatry 45 (3) • May-Jun 2023 • https://doi.org/10.47626/1516-4446-2023-3044 copy

A dopamine receptor D2 genetic polymorphism associated with transition to mental disorders in a cohort of individuals with at-risk mental state for psychosis

Authorship SCIMAGO INSTITUTIONS RANKINGS

Objectives:

To test the association of 45 single nucleotide polymorphisms (SNPs) with transition to psychiatric disorders in a cohort of individuals at ultrahigh risk (UHR) mental state for psychosis.

Methods:

Through general population screening, 88 non-help-seeking UHR subjects and 130 healthy control individuals were genotyped for 45 SNPs related to psychosis. They were followed for a mean of 2.5 years, and conversion to psychotic and to general psychiatric disorders was assessed. Genotype frequencies between controls, converters, and non-converters were analyzed.

Results:

There were no differences in sociodemographics between controls and UHR. Also, UHR converters and non-converters had no differences in their baseline symptoms scores. The dopamine receptor D2 gene (DRD2) SNP rs6277 was significantly more common among UHR who transitioned to psychosis (p < 0.001) and to UHR who transitioned to any psychiatric disorders (p = 0.001) when compared to UHR who did not transition. The rs6277 T allele was related to psychiatric morbidity in a dose-response fashion, being significantly more frequent in UHR converters than UHR non-converters and control subjects (p = 0.003).

Conclusion:

Our findings suggest that rs6277 could potentially constitute a genetic marker of transition to psychiatric disorders in subjects with at-risk mental states, warranting further investigation in larger samples.

Dopamine; schizophrenia; clinical high risk; flip-flop; attenuated psychosis

	UHR converters	UHR non-converters	Controls
Variables	(n=16)	(n=72)	(n=130)	p-value^† † For all significant p-values described, post-hoc analysis indicated no significant difference between UHR groups, but significant differences between both and controls.
Sex, female	9 (56.3)	49 (68.1)	74 (56.9)	0.281
Socioeconomic class C, middle income	10 (62.5)	39 (55.7)	73 (57.0)	0.565
Age, mean (SD)	25.3 (4.2)	24.6 (4.0)	25.2 (4.3)	0.602
Education, mean (SD)	10.5 (2.6)	10.9 (1.9)	11.0 (2.1)	0.670
SIPS, mean (SD)
P1 - Unusual thought content/delusional ideas	2.4 (1.7)	2.1 (1.5)	0.6 (0.8)	< 0.001
P2 - Suspiciousness/persecutory ideas	2.9 (1.4)	2.3 (1.4)	0.7 (0.9)	< 0.001
P3 - Grandiosity	0.4 (0.8)	0.4 (0.8)	0.3 (0.7)	0.572
P4 - Perceptual abnormalities/hallucinations	3.5 (1.3)	2.9 (1.8)	0.6 (0.9)	< 0.001
P5 - Disorganized communication	0.7 (1.1)	0.5 (1.0)	0.2 (0.6)	0.027
N1 - Social anhedonia	0.9 (1.1)	1.3 (1.6)	0.2 (0.7)	< 0.001
N2 - Avolition	1.2 (1.5)	0.9 (1.4)	0.2 (0.6)	< 0.001
N3 - Expression of emotion	0.8 (1.0)	0.5 (0.9)	0.1 (0.4)	< 0.001
N4 - Experience of emotions and self	0.9 (1.0)	0.7 (1.0)	0.2 (0.7)	< 0.001
N5 - Ideational richness	0.8 (0.8)	1.5 (1.6)	0.6 (1.1)	< 0.001 ^‡ ‡ On post-hoc analysis, controls and UHR converters did not differ, but both differed from UHR non-converters.
N6 - Occupational functioning	0.8 (1.4)	0.6 (1.1)	0.2 (0.6)	0.004
D1 - Odd behavior and appearance	0.1 (0.3)	0.4 (0.8)	0.1 (0.5)	0.029 ^‡ ‡ On post-hoc analysis, controls and UHR converters did not differ, but both differed from UHR non-converters.
D2 - Bizarre thinking	0.4 (0.9)	0.3 (0.7)	0.0 (0.2)	0.016
D3 - Trouble with focus and attention	1.6 (1.4)	1.6 (1.4)	0.6 (1.0)	< 0.001
D4 - Personal hygiene	0.2 (0.6)	0.2 (0.7)	0.0 (0.0)	0.030
G1 - Sleep disturbance	2.0 (1.7)	1.3 (1.5)	0.6 (0.9)	< 0.001
G2 - Dysphoric mood	2.3 (1.4)	1.9 (1.5)	0.9 (1.3)	< 0.001
G3 - Motor disturbances	0.3 (0.7)	0.3 (0.6)	0.1 (0.3)	0.026
G4 - Impaired tolerance to normal stress	2.0 (1.3)	1.4 (1.5)	0.8 (1.7)	0.005
GAF - Global assessment of functional scale	62.9 (13.9)	70.9 (12.3)	81.2 (8.3)	< 0.001
UHR syndromes^§ § Not mutually exclusive.
APS	15 (93.7)	67 (93.1)	-	0.522
BIPS	1 (6.3)	5 (6.9)
GRD	1 (6.3)	1 (1.4)

	UHR-C	Controls + UHR-NC		UHR-C	UHR-NC
Variable	(n=16)	(n=205)	p-value	(n=16)	(n=72)	p-value
Rs6277
TT	43.8^a a,b Same superscript letter denotes groups that did not differ significantly.	11.6^b a,b Same superscript letter denotes groups that did not differ significantly.	0.001	43.8^b a,b Same superscript letter denotes groups that did not differ significantly.	7.4^a a,b Same superscript letter denotes groups that did not differ significantly.	< 0.001
CT	37.5^a a,b Same superscript letter denotes groups that did not differ significantly.	45.5^a a,b Same superscript letter denotes groups that did not differ significantly.		37.5^a a,b Same superscript letter denotes groups that did not differ significantly.	49.5^a a,b Same superscript letter denotes groups that did not differ significantly.
CC	18.8^a a,b Same superscript letter denotes groups that did not differ significantly.	42.9^a a,b Same superscript letter denotes groups that did not differ significantly.		18.8^a a,b Same superscript letter denotes groups that did not differ significantly.	44.1^a a,b Same superscript letter denotes groups that did not differ significantly.

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[1] Correspondence: Alexandre Andrade Loch, Instituto de Psiquiatria, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, Rua Dr. Ovídio Pires de Campos, 785, 4° andar, sala 4N60, CEP 05403-903, São Paulo, SP, Brazil. E-mail: alexandre.loch@usp.br