Serotonin gene polymorphisms and bipolar I disorder: Focus on the serotonin transporter

Figures & data

Table I. Published BD1 case‐control association studies using SLC6A4 polymorphisms.

Reference	Marker	Ethnicity	Cases	Controls	Dx	Comment
66	VNTR	Caucasian+not  specified	252	187	DSM‐IV	Association with 12 repeat allele  (P = 0.00048, allele‐wise)
67	VNTR	Caucasian	124	121	DSMIII‐R	Association with 12 repeat allele
104	VNTR	Japanese	98	137	RDC	NS
105	VNTR	Caucasian	79	86	DSMIII‐R	NS
99	VNTR 5‐ HTTLPR	Caucasian	79	294	DSM‐IV SADS‐LA	NS
101	VNTR 5‐HTTLPR	Spanish	88	113	DSMIII‐R	NS
72	VNTR 5‐HTTLPR	Sample 1 Caucasian	87	174	RDC	NS
		Sample 2 Caucasian	375 392	772 739	DSM‐IV	Meta‐analysis: Significant association with  5‐HTTLPR allele 2 (chi‐square  = 3.68, d.f. = 1, P = 0.049, OR 1.21)
106	VNTR 5‐HTTLPR	British Caucasian	171	121	DSM‐IV	NS with 5‐HTTLPR. VNTR, Association  with 12 repeat allele (P = 0.031)
69	5‐HTTLPR VNTR	Caucasian	208	99	DSM‐IV	Association with homozygosity for short  variant of 5‐HTTLPR (chi‐square  = 4.68, d.f. = 1, P = 0.03, OR 2.11)
107	5‐HTTLPR	Mixed*	47	98	DSM‐IV	NS
18	VNTR 5‐HTTLPR	Sample 1 Mixed**	103	103	RDC	NS
		Sample 2 Caucasian	109	109
97	5‐HTTLPR	Colombian	103	112	DIGS	NS. Excess short allele in younger cases  and in cases with psychotic symptoms.
108	VNTR	Indian	50	50	ICD‐10	NS
98	5‐HTTLPR	Caucasian	572	821	SCAN SADS‐LA	NS
74	5‐HTTLPR VNTR+10 SNPs	Japanese	61 (BD1)	288	DSM‐IV	NS

Dx = diagnostic criteria; DSM = Diagnostic and Statistical Manual for Mental Disorders; RDC = research diagnostic criteria; DIGS = Diagnostic Interview for Genetic Studies; SCAN = Schedule for Clinical Assessment of Neuropsychiatry; SAD‐LA = Schedule for Affective Disorders and Schizophrenia–lifetime version; VNTR = variable number of tandem repeat polymorphism in the second intron; 5HTTLPR = insertion/deletion polymorphism in the 5' upstream regulatory region; NS = ot significant; BD1 = bipolar 1 disorder; * 80% Caucasian and 20% African/Brazilian; ** 95% Caucasian, 3% Oriental, and 2% Native Canadian.

Table II. Association and linkage analysis of ploymorphisms at SLC6A4 using Pittsburgh BD1 sample.

	Marker	Allele	Position in bp*	Frequency of less common allele		Trends test (P value)	TDT T/NT
				cases	controls
1	rs140701	C/T	3275525	0.406	0.425	0.668	28/28
2	rs2020942	G/A	3283907	0.399	0.377	0.586	25/26
3	rs6354	G/T	3286891	0.192	0.198	0.839	16/17
4	rs2020939	G/A	3287725	0.414	0.419	0.910	29/28
5	rs2020937	A/T	3287750	0.396	0.377	0.640	26/25
6	rs2066713	G/A	3288658	0.399	0.375	0.539	25/26
7	rs2020935	A/T	3298448	0.077	0.058	0.340	5/5
8	rs2020934	C/T	3298453	0.496	0.477	0541	16/26
9	rs2020933	A/T	3298748	0.06	0.061	0.954	4/4
10	rs25532	C/T	3301163	0.162	0.141	0.483	11/11
11	5‐HTTLPR	L/S	3301301..3301344	0.452	0.458	0.884	18/24
12	rs2020930	G/A	3303034	0.042	0.036	0.658	4/3

*Genomic sequence, including exons and introns (www.ncbi.nlm.nih.gov, build 34, version 2). TDT = transmission disequilibrium test; T/NT = transmitted/non‐transmitted, this refers to the first allele in column 3; L/S = long allele/short allele; No significant differences were observed using Trends test for case‐control analysis or TDT for family‐based analysis.

Figure 1. Structure ofSLC6A4 gene and polymorphisms analyzed.

Figure 2. LD Pattern using H‐Clust analysis: Controls from the Pittsburgh sample.

Table III. Association analysis of polymorphisms at SLC6A4 using the STEP‐BD sample.

	Marker	Allele	Position in bp*	Frequency of less common allele		Trends test (P value)
				cases	Controls
1	rs140701	C/T	3275525	0.432	0.427	0.816
2	rs2020942	G/A	3283907	0.391	0.384	0.736
3	rs6354	G/T	3286891	0.183	0.202	0.288
4	rs2020939	G/A	3287725	0.432	0.427	0.812
5	rs2020937	A/T	3287750	0.394	0.383	0.606
6	rs2066713	G/A	3288658	0.392	0.383	0.640
7	rs2020935	A/T	3298448	0.057	0.067	0.307
8	rs2020934	C/T	3298453	0.488	0.480	0.705
9	rs2020933	A/T	3298748	0.049	0.066	0.093
10	rs25532	C/T	3301163	NA	NA	NA
11	5‐HTTLPR	L/S	3301301…3301344	0.439	0.428	0.629
12	rs2020930	G/A	3303034	0.033	0.042	0.278

*Genomic sequence, including exons and introns (www.ncbi.nlm.nih.gov, build 34, version 2). L/S = long allele/short allele; NA = not analyzed. No significant differences were observed using Trends test for case‐control analysis.

Table IV. Linkage disequilibrium across SLC6A4 using D' and r² values among Pittsburgh BD1 cases.

Polymorphism	rs140701	rs2020942	rs6354	rs2020939	rs2020937	rs2066713	rs2020935	rs2020934	rs2020933	rs25532	5hTTLPR	rs2020930
rs140701	\	0.98	0.94	0.99	0.98	0.98	0.74	0.8	0.86	0.59	0.45	1
rs2020942	0.48	\	0.95	1	1	1	0.76	0.79	0.35	0.33	0.63	0.44
rs6354	0.13	0.13	\	0.95	0.95	0.95	0.73	0.11	0.73	1	0.05	0.79
rs2020939	0.97	0.5	0.13	\	1	1	0.74	0.78	0.86	0.57	0.45	1
rs2020937	0.49	0.99	0.14	0.51	\	1	0.76	0.79	0.37	0.34	0.63	0.46
rs2066713	0.49	0.99	0.14	0.51	1	\	0.76	0.79	0.37	0.34	0.63	0.46
rs2020935	0.03	0.03	0.2	0.03	0.03	0.03	\	1	0.94	1	0.74	1
rs2020934	0.49	0.4	0	0.48	0.41	0.41	0.06	\	1	0.95	0.76	1
rs2020933	0.03	0.01	0.16	0.03	0.01	0.01	0.8	0.05	\	1	0.68	1
rs25532	0.08	0.01	0.03	0.07	0.01	0.01	0.01	0.16	0.01	\	0.91	1
5hTTLPR	0.2	0.2	0	0.2	0.2	0.2	0.03	0.44	0.02	0.19	\	0.58
rs2020930	0.03	0.01	0.11	0.03	0.01	0.01	0.48	0.03	0.57	0.01	0.01	\

D' and r² values are shown above and below the diagonal (\) respectively 88.

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