Table 2.

Single nucleotide polymorphisms (SNPs) in purinergic genes implicated in mood disorders

Genetic Variant and Poly- morphism	Findings	Sample size	Mood Disorders	Correc- tions	Gene coverage	Subject criteria	Study type & phenotype definition	Fin- dings	References
P2X7
P2X7: rs2230912 Gln460Arg	Not associated with diagnosis. BD subjects with at least one allele had higher symptom severity	315	BD and MDD	Bonferroni; adjusted for gender on HADS	GWAS (assessed multiple genotypes)	DSM-IV by psychiatrists	Case-control, symptom severity (MADRS and HDRS scores)	+/−	(Halmai et al., 2013)
	Associated with length of current mood episode, which was moderated by neurotic traits	424	BD and MDD	Based on (Soronen et al., 2011)	Based on (Soronen et al., 2011); gene specific	Semi-structured interview	Length of episode moderated by neurotic traits	+	(Mantere et al., 2012)
	Associated with rapid cycling BD diagnosis	690 (n=569 BD-I, n=121 rapid cycling)	BD only	Correction by permutation tests; gender-confounder adjusted	3 SNPs	Lifetime assessment for specific symptoms, medical records, and interviews	Manic symptoms, then case-case	+	(Backlund et al., 2011)
	Associated with family history of mood disorders Associated with longer duration of illness Note: the same finding was seen with the rs208294 SNP, see below*	450 (n=178 BD, n=272 MDD)	BD and MDD	Gender and age adjustment	Specific allelic association analyses	Semi-structured interview	Case-control, post-hoc by diagnosis, family history, duration of illness	+	(Soronen et al., 2011)
	Not associated with diagnosis Not associated with symptom profile	457	Depression (including MDD, dysthymia, and mixed anxiety depression)	Adjusted for gender and age	Specific allelic association analysis	DSM-IV by MDI	Case-control; multiple scales (anxiety, obsessive- compulsive, depression, eating disorders, disability, alcohol abuse, well-being, environmental risks)	−	(Lavebratt et al., 2010)
	Associated with diagnosis of BD	604	BD only	Not corrected	Specific allelic association analysis	Structured interview	Case-control	+	(McQuillin et al., 2009)
	Associated with increased symptom severity (both depression and anxiety) in both BD and MDD	171	BD and MDD	Adjusted for gender and age	Specific allelic association analysis	DSM-IV	Case control, then symptom severity (HADS)	+	(Hejjas et al., 2009)
	Not associated with diagnosis	1445 (European cohort)	BD and MDD	Corrected by permutations	Single marker association analysis	Structured interview	Case-control	−	(Grigoroiu-Serbanescu et al., 2009)
	Not associated with diagnosis	1723 (n=687 BD, n=1036 MDD)	BD and MDD	Bonferroni; adjusted for gender and age	Specific allelic association analysis	DSM-IV and semi-structured interview	Case-control, familial study	−	(Green et al., 2009)
	Associated with increased symptom severity	218	Diabetics with mixed symptoms of anxiety and depression	False discovery rate correction	Specific allelic association analysis	Symptoms assessed by HADS	Case-case, symptom severity	+	(Nagy et al., 2008)
	Associated with diagnosis of depression	1000	MDD only	False discovery rate correction, then correction by permutation	Specific allelic association analysis	DSM-IV and semi-structured interview	Case-control	+	(Lucae et al., 2006)
	Associated with diagnosis of BD	485	BD only	Adjusted p-value in stats package vs. expected frequency of alleles	Specific allelic association analysis, linkage analysis	Structured interview	Case-control, familial study	+	(Barden et al., 2006)
P2X7: rs208294 His155Tyr	Associated with family history of mood disorders Associated with longer duration of illness Note: same finding as rs2230912 SNP, see above*	450	BD and MDD	Adjusted for gender and age	Specific allelic association analysis	Semi-structured interview	Case-control, post-hoc by diagnosis, family history, duration of illness	+	(Soronen et al., 2011)
	Not associated with diagnosis of MDD Not associated with treatment (ECT vs. SSRI)	613 (n=218 with MDD)	MDD only	Adjusted for gender and age	Specific allelic association analyses	DSM-IV, MADRS	Case-control, Case-case, MADRS score change	−	(Viikki et al., 2011)
P2X7: rs171811 Thr348Ala	Associated with symptoms of cognitive impairment, distractibility, talkativeness, and thought disorder	690	BD only	Correction by permutation tests, adjusted for gender	3 SNPs	Lifetime assessment for specific symptoms, medical records, and interviews	Case-case by manic symptoms	+	(Backlund et al., 2011)
	Trend towards an association with symptom severity for panic and agoraphobia	179 pts, 462 controls	Anxiety disorders (including panic disorder and agoraphobia)	Correction by permutation tests, adjusted for gender	25 SNPs	Structured interviews	Case-control, symptom severity by panic and agoraphobia scale	~	(Erhardt et al., 2007)
P2X7: rs1653625 AA (not AC or CC) in the 3′ un- translated region of the P2RX7 gene	Not associated with diagnosis of MDD or mood state in MDD subjects The association between this SNP and depressive symptoms in BD did not survive correction	315 (n=195 MDD, n=120 BD)	BD and MDD	Bonferroni and adjusted for gender on HADS	GWAS (assessed multiple genotypes)	DSM-IV by psychiatrists	Case-control, symptom severity (MADRS and HDRS score)	−/~	(Halmai et al., 2013)
Other Purinergic SNPs
A2aAR: 1976C/T A2A receptor	Not associated with a mood disorder diagnosis	192 patients (408 total)	BD and MDD	No	Single marker association analysis	DSM-IV criteria	Case-control	−	(Tsai et al., 2006)
	Not associated with a diagnosis of panic disorder	104 pts, 192 controls (Chinese cohort)	Panic disorder	No	Single marker association analysis	Semi- structured interview	Case-control	−	(Lam et al., 2005)
	Associated with symptoms of panic disorder and agorophobia	70 subjects from pedigree, 83 familialtrios	Panic disorder	No	Haplotype combinations of 14 SNPs	Semi-structured interview	Familial pedigree study, panic disorder and agoraphobia scale	+	(Hamilton et al., 2004)
	Associated with greater anxiety after caffeine challenge (also with the 2592T/T A2A receptor SNP)	100	No mood disorder history	No	4 loci of the A2A receptor	Telephone and in person screen	All healthy, double-blind study	+	(Alsene et al., 2003)
Mito-chondrial DNA 5178	Associated with diagnosis of BD Associated with higher intracellular pH in BD subjects	145 patients, 184 controls	BD only	No	Single marker association analysis	DSM-IV by two psychiatrists	Case-control	+	(Kato et al., 2000)
SLC29A3, rs12256138 Variation in nucleoside (including adenosine) transporter gene transport	Associated with a diagnosis of depression or sleep disturbance	1423 (cohort of Finnish women)	MDD and symptoms of sleep disturbance	Bonferroni and adjusted for gender	117 SNPs from 13 genes	Structured interview	Case-control	+	(Gass et al., 2010)
GNB3, C825T poly-morphism G-protein B3 subunit	Associated with antidepressant response	Meta-analysis	Depression (varied)	Varied	Single marker association analysis	Varied	Varied	+	(Klenke et al., 2011)

⁺indicates a positive association between the SNP and disease risk or a related phenotype

⁻indicates no association between the SNP and disease risk or a related phenotype

^~Trend towards an association between the SNP and disease risk or a related phenotype

Abbreviations: BD: bipolar disorder; MDD: major depressive disorder; SNP: single nucleotide polymorphism; HDRS: Hamilton Depression Rating Scale, MADRS: Montgomery-Asberg Depression Rating Scale; MDI: Major Depressive Inventory; HADS: Hospital Anxiety and Depression Scale; GWAS: genome-wide association study; SSRI: selective serotonin reuptake inhibitor; ECT: electroconvulsive therapy.