Study Report

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Basic Info

Reference	Lim C.H., 2014 PMID: 24914473
Citation	Lim, C. H., et al. (2014). "Genetic association of LMAN2L gene in schizophrenia and bipolar disorder and its interaction with ANK3 gene polymorphism." Prog Neuropsychopharmacol Biol Psychiatry.
Disease Type	Bipolar Disorder & Schizophrenia
Study Design	case-control
Study Type	Candidate-gene association study
Sample Size	715 patients (244 BPD and 471 SZ) and 593 controls
SNP/Region/Marker Size	5 SNPs
Predominant Ethnicity	Mongloid
Population	Malays, Chinese and Indians
Gender	Biopolar disorder: 128 (53%) male and 116 (48%) female; Controls: 375 (63%) male and 218 (37%) female
Age Group	adults : Bipolar disorder: mean=43.0, SD=12.0; Controls: mean=41.1, SD=10.3

Detail Info

Sample Diagnosis	All patients were diagnosed through consensus by at least two experienced psychiatrists, according to the criteria for BPD and SZ, as set out by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.
Sample Status	The patients were from the psychiatry outpatient clinic of UMMC. Most of the BPD patients (90%) were BPD Type I patients and all were in euthymic state during the period of sample collection.
Technique	genotyped using the Sequenom Mass ARRAY platform with iPLEX Gold chemistry (Sequenom, San Diego, CA, USA) according to the manufacturer's protocols.
Statistical Method	The genotype distribution was assessed for Hardy-Weinberg equilibrium (HWE) using a _² test. Determination of allele association was performed by using logistic regression. Linkage disequilibrium(LD) and haplotype analysis were performed with the Haploview 4.2 program. Pairwise LDwas used to investigate the inter-marker relationship through D' values in case and control subjects. A permutation test with 5000 replications was used to obtain empirical levels of significance. To investigate the influence of gene-gene interaction on BPD and SZ, the Generalized Multifactor Dimensionality Reduction(GMDR) method was employed.
Result Summary	We showed a positive association between LMAN2L (rs6746896) and risk of both BPD and SZ in a pooled population (P-value= 0.001 and 0.009, respectively). Following stratification by ethnicity, variants of the ANK3 gene (rs1938516 and rs10994336)were foundto be associated with BPD in Malays (P-value= 0.001 and0.006, respectively). Furthermore, an association exists between another variant of LMAN2L (rs2271893) and SZ in the Malay and Indian ethnic groups (P-value= 0.003 and 0.002, respectively). GeneÃ�gene interaction analysis revealed a significant interaction between the ANK3 and LMAN2L genes (empirical P= 0.0107). Significant differences were shown between patients andcontrols for two haplotype frequencies of LMAN2L:GA(P= 0.015 and P= 0.010, for BPD and SZ, respectively) and GG (P=0.013 for BPD).

Genetic factors reported by this study for BD

SNPs reported by this study for BD (count: 5)

SNP	Related Gene(s)	Allele Change	Risk Allele	Statistical Values	Author Comments	Result Category
rs6746896	LMAN2L CNNM4	A/G	G	All ethnicities: OR=1.36, 95%CI =1.08-1.71, P-value=0.009; Malay: OR=1.09, 95%CI =0.74-1.60, P-value=0.678; Chinese: OR=1.63, 95%CI =1.14-2.34, P-value=0.007; Indian: OR=1.21, 95%CI =0.73-2.00, P-value=0.471	rs6746896 shows significant differences in allelic distribut...... rs6746896 shows significant differences in allelic distribution between both BPD and SZ patients and controls for the pooled subjects (P =0.009 and 0.001, respectively). More...	Positive
rs1938526	ANK3	T/C	C	All ethnicities: OR=0.92, 95%CI =0.72-1.17, P-value=0.483; Malay: OR=0.47, 95%CI =0.30-0.74, P-value=0.001; Chinese: OR=0.92, 95%CI =0.64-1.32, P-value=0.646; Indian: OR=2.03, 95%CI =1.15-3.58, P-value=0.015	ANK3 rs1938526 was associated with BPD in Indians (P = 0.015...... ANK3 rs1938526 was associated with BPD in Indians (P = 0.015). More...	Positive
rs2271893	LMAN2L	G/A	A	All ethnicities: OR=1.12, 95%CI =0.85-1.48, P-value=0.429; Malay: OR=0.83, 95%CI =0.49-1.41, P-value=0.490; Chinese: OR=1.15, 95%CI =0.77-1.71, P-value=0.495; Indian: OR=1.31, 95%CI =0.73-2.30, P-value=0.363	No significant association was observed. No significant association was observed.	Negative
rs2073831	BTF3P11 KCTD12	C/T	T	All ethnicities: OR=0.99, 95%CI =0.80-1.23, P-value=0.94; Malay: OR=0.90, 95%CI =0.40-1.35, P-value=0.602; Chinese: OR=0.92, 95%CI =0.07-1.26, P-value=0.612; Indian: OR=1.16, 95%CI =0.74-1.80, P-value=0.524	No significant association was observed. No significant association was observed.	Negative
rs10994336	ANK3	C/T	T	All ethnicities: OR=1.01, 95%CI =0.76-1.33, P-value=0.976; Malay: OR=0.49, 95%CI =0.30-0.81, P-value=0.006; Chinese: OR=1.19, 95%CI =0.76-1.86, P-value=0.439; Indian: OR=1.81, 95%CI =1.01-3.26, P-value=0.047	rs10994336 was significantly different between BPD and SZ pa...... rs10994336 was significantly different between BPD and SZ patients and controls of Malay ethnicity(P= 0.001 and 0.012, for BPD and SZ, respectively). More...	Positive

Genes reported by this study for BD (count: 3)

Gene	Statistical Values/Author Comments	Result Category
ANK3	Following stratification by ethnicity, variants of the ANK3 gene (rs1938526 and rs10994336) were fou...... Following stratification by ethnicity, variants of the ANK3 gene (rs1938526 and rs10994336) were found to be associated with BPD in Malays (P-value=0.001 and0.006, respectively). More...	Positive
KCTD12	The associated SNP in this gene showed no significant association with BD. The associated SNP in this gene showed no significant association with BD.	Negative
LMAN2L	A positive association between LMAN2L (rs6746896) and risk of both BPD and SZ in a pooled population...... A positive association between LMAN2L (rs6746896) and risk of both BPD and SZ in a pooled population (P-value=0.009 and 0.001, respectively). More...	Positive

Genetic factors reported by this study for SZ and/or MDD

SNPs reported by this study for SZ/MDD

Disease	SNP	Related Gene(s)	Statistical Values	Description	Result Category
SZ	rs10994336	ANK3	All ethnicities: OR=0.98, 95%CI =0.78-1.23, P-value=0.840; Malay: OR=0.62, 95%CI =0.40-0.95, P-value=0.029; Chinese: OR=1.05, 95%CI =0.76-1.46, P-value=0.776; Indian: OR=1.45, 95%CI =0.91-2.32, P-value=0.116	rs10994336 was significantly different between BPD and SZ patients and controls of Malay ethnicity(P= 0.001 and 0.012, for BPD and SZ, respectively).	Positive
SZ	rs2073831	BTF3P11 KCTD12	All ethnicities: OR=1.07, 95%CI =0.90-1.28, P-value=0.445; Malay: OR=0.68, 95%CI =0.49-0.95, P-value=0.025; Chinese: OR=1.35, 95%CI =1.04-1.74, P-value=0.024; Indian: OR=1.18, 95%CI =0.81-1.70, P-value=0.387	KCTD12 rs2073831 was significantly associated with SZ in Malays and Chinese (P= 0.024 and 0.025, respectively).	Positive
SZ	rs2271893	LMAN2L	All ethnicities: OR=1.24, 95%CI =0.99-1.56, P-value=0.060; Malay: OR=2.63, 95%CI =1.40-4.97, P-value=0.003; Chinese: OR=0.86, 95%CI =0.64-1.15, P-value=0.297; Indian: OR=2.76, 95%CI =1.46-5.20, P-value=0.002	rs2271893 C allele frequency was significantly higher in SZ patients compared with healthy controls, a condition observed in Malays and Indians (P= 0.002 and P= 0.003, respectively).	Positive
SZ	rs1938526	ANK3	All ethnicities: OR=0.86, 95%CI =0.71-1.04, P-value=0.123; Malay: OR=0.60, 95%CI =0.41-0.89, P-value=0.012; Chinese: OR=0.87, 95%CI =0.66-1.15, P-value=0.334; Indian: OR=1.21, 95%CI =0.79-1.83, P-value=0.384	rs1938526 was found to be significantly associated with BPD and SZ.	Positive
SZ	rs6746896	LMAN2L CNNM4	All ethnicities: OR=1.34, 95%CI =1.12-1.61, P-value=0.001; Malay: OR=1.50, 95%CI =1.07-2.10, P-value=0.020; Chinese: OR=1.21, 95%CI =0.94-1.55, P-value=0.148; Indian: OR=1.59, 95%CI =0.98-2.58, P-value=0.061	rs6746896 shows significant differences in allelic distribution between both BPD and SZ patients and controls for the pooled subjects (P =0.009 and 0.001, respectively).	Positive

Genes reported by this study for SZ/MDD

Disease	Gene	Description	Result Category
SZ	ANK3	rs1938526 and rs10994336 of the ANK3 gene were found to be significantly associated with BPD and SZ.	Positive
SZ	LMAN2L	A positive association between LMAN2L (rs6746896) and risk of both BPD and SZ in a pooled population (P-value= 0.001 and 0.009, respectively).	Positive
SZ	KCTD12	KCTD12 rs2073831 was significantly associated with SZ in Malays and Chinese (P= 0.024 and 0.025, respectively).	Positive