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From SNPedia

Geno Mag Summary
(C;C) complex; possible association with anxiety related behaviours
(C;G) complex; possible association with anxiety related behaviours
(G;G) complex; possible association with anxiety related behaviours
ReferenceGRCh38 38.1/141
is asnp
is mentioned by
dbSNP (classic)rs4606
1000 genomesrs4606
23andMe allrs4606
GWAS Ctlgrs4606
Max Magnitude0

In mice, the genetic locus best correlated to anxiety-related behaviour contains the 'regulator of G protein signaling 2' gene [PMID 15489855]. In humans, SNPs in the equivalent RGS2 gene have now been studied to see if they are correlated to anxiety related disorders.[PMID 18316676]

In the first part of one study, 119 families including children underwent standard lab-based behavioural assessments of behavioural inhibition, defined as a heritable temperamental profile characterized by a tendency to be shy, avoident, and behaviourally restrained in situations that are novel or unfamiliar. Along with some other RGS2 SNPs, carriers of a rs4606(G) allele were 3 fold more likely to exhibit behavioural inhibition (CI: 1.31-6.84, p = 0.0026).

In the second part of this study, 744 college undergraduates (228 men, 516 women) who had been genotyped completed a personality profile known as the NEO-E (introversion) association test. Consistent with the earlier results, the same RGS2 alleles associated with behavioural inhibition were significantly (p < 0.05) associated with introversion (but not neuroticism), including rs4606(G), rs6428136(G), and rs10801152(T).

In the third part of this study, 55 female undergraduates were studied by fMRI (functional MRI) emotional processing tests. Carriers of SNPs rs4606(G) or rs10801152(T) showed increased insular cortex activation, a reflection of anxiety, in these tests.

Based on these results, the authors predict that social anxiety disorder is the most likely anxiety disorder to be associated with SNPs in the RGS2 gene such as rs4606.

[PMID 18316676] SNPs in the RGS2 gene, including rs4606, show association with childhood temperament, adult personality, and brain function.

[PMID 18833580OA-icon.png] each rs4606(C) allele was associated with a 2x (p =.026) increased risk of generalized anxiety disorder.

[PMID 16736243] 173 patients with panic disorder (and 173 matched controls) of German descent analyzed, leading to the conclusion that rs4606(G) carriers were at ~2x increased risk for this disorder. Note that the (G) allele appears to be the minor (rarer) allele in this study.

Note: given the conflicting reports over whether the (C) or (G) allele is implicated in anxiety-related disorders, Dr. Jordan Smoller was contacted to verify that the orientation was unambiguously reported in the various publications. He has confirmed that the reports truly vary in which allele is considered the risk allele; this may be an example of the "flip-flop" phenomenon [PMID 17273975OA-icon.png].

rs4606 has also been reported to be associated with the development of Parkinson's like symptoms in schizophrenia patients treated with various drugs, as follows:

[PMID 18347610] A replication study was performed in which extrapyramidal symptoms (EPS) were rated in 184 US patients with schizophrenia. This group (115 African Americans, 69 Caucasian) was treated for at least a month with typical antipsychotic drugs (n=45), risperidone (n=46), olanzapine (n=50) or clozapine (n=43). The minor (G) allele showed a protective effect against antipsychotic-induced parkinsonism (AIP), with an odds ratio for AIP among rs4606(G) carriers of 0.23 (CI: 0.10-0.54, p=0.001) for the overall sample.

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[PMID 17558307] 121 consecutively hospitalized, psychotic patients with Diagnostic and Statistical Manual of Mental Disorder-IV schizophrenia receiving treatment with typical antipsychotic medication (n=72) or typical antipsychotic drugs and risperidone (n=49) for at least 2 weeks were studied. After correction for multiple testing the only RGS2 SNP associated with development or worsening of parkinsonian symptoms was rs4606 (p=0.002).

[PMID 19162436OA-icon.png] rs4606 modifies risk of postdisaster and lifetime post-traumatic stress disorder symptoms under conditions of high stressor exposure

[PMID 19156702] Lack of association between antipsychotic-induced Parkinsonism or its subsymptoms and rs4606 SNP of RGS2 gene in African-Caribbeans and the possible role of the medication: the Curacao extrapyramidal syndromes study X.

[PMID 19813112OA-icon.png] Variation in RGS2 is associated with suicidal ideation in an epidemiological study of adults exposed to the 2004 Florida hurricanes

[PMID 17728697] Association of RGS2 gene polymorphisms with suicide and increased RGS2 immunoreactivity in the postmortem brain of suicide victims.

[PMID 18262772OA-icon.png] Association of RGS2 and RGS5 variants with schizophrenia symptom severity.

[PMID 19931593] Association analysis between functional polymorphism of the rs4606 SNP in the RGS2 gene and antipsychotic-induced Parkinsonism in Japanese patients with schizophrenia: results from the Juntendo University Schizophrenia Projects (JUSP).

[PMID 21438143] Association of RGS2 variants with panic disorder in a Japanese population.

[PMID 21737952] Genetic variation in gsalpha protein as a new indicator in screening test for vasovagal syncope.

[PMID 23339167] Single nucleotide polymorphisms in G protein signaling pathway genes in preeclampsia.

[PMID 25740197] RGS2 ggenetic variation: Association analysis with panic disorder and dimensional as well as intermediate phenotypes of anxiety