BPD is a common disease that is genetically heterogeneous with the same clinical manifestation caused by different susceptibility genes or a combination of low penetrating genes with possible environmental effect. Analysis using mathematical modelling suggests the heterogeneous basis for the inheritance of bipolar disorders [36
]. For investigating these complex phenotypic traits like BPD, current studies suggest that using association analysis can have acceptable power to identify these small genetic effects [37
This study aims to investigate the MAOA gene effect on BPD etiology in Han Chinese. The genetic association between two polymorphisms of the MAOA gene and BPD was conducted in 108 BPI patients and 103 normal controls. To overcome the sample size limitation for detecting small risk effect, we consider the two risk allele at the same time and examine if there are any additive or interactive risk for BPD. Growing evidences have supported the existence of higher-order risk interactions between or within genes to cause common and complex diseases [33
]. Previous study also showed a combination of several common variants, that an association with disease at single-locus levels are not significant, has a dramatic impact on the etiology of complex diseases [33
]. Using the haplotype based interaction-considered approach; we successfully identified a risk haplotype for BPD.
Significant risk haplotype effect was detected in male groups but not in female groups. Our hypothesis of the male-specific effect is the male only have single copy of MAOA
, thus the carrying of risk haplotype lead more contribution to the diseased state. The gender effect of MAOA in various psychiatric diseases has been discussed for a long while. The first mutation in MAOA related to abnormal behavior was seen in several males [8
]. The MAOA deficiency was associated with increased aggression; a similar finding was made in male mice [10
]. In addition, many studies have reported finding significant gender-specific associations with psychiatric diseases [14
] including BPD [27
]. Collectively, these results suggest that the MAOA mechanism underlying the etiology of BPD might be different in males and females.
Just like other common psychiatric syndromes, BPD is known to have complex etiology including effect of multiple pathogenic genes and non-genetic factors [41
]. The controversial results from previous association studies in various populations [22
] suggest the MAOA gene and/or its interacting factors may have ethnic specificity in BPD etiology. Although the risk haplotype of MAOA
only carried by few BPD patients and suggests that MAOA gene may have only a small effect on the pathogenesis of BPD, other studies have correlated MAOA with many human behavioral traits that belong to the same spectrum with BPD, including aggression [8
], anxiety [42
], depression [14
], and suicide [43
]. Furthermore, the MAOA-knockout mice showed aggressive behavior, which indicates a major effect of MAOA deficiency. Taken together, these results strongly suggest that MAOA is indeed involved in the spectrum of diseases related to abnormalities of the central nervous systems; however, the effect of MAOA on different diseases seems to be dissimilar.
Earlier studies indicated that there were 5 alleles of the uVNTR polymorphism (2, 3, 3.5, 4, and 5; 30-bp repeats), allele 3, 3.5, 4, and 5 were found in German population [44
], and in White/Non-Hispanic and African-American/Black genotyping studies [18
]. Another rare allele that has two 30-bp repeats was found in Japanese, British Caucasian, Swedish and Italian population [44
]. Furthermore, the long alleles (4 and 5, 30-bp repeat) have been reported to be transcriptionally more active than the short allele (3, 30-bp repeat) [18
]. In the present study, we detected 3 alleles (3, 4, and 5) in people of Han Chinese origin in Taiwan, and the major alleles are 3 and 4 repeats. The observed allele distribution in this study is similar to another report from Taiwan [14
] and to a report from the People's Republic of China [48
]; all three together suggest that this unique distribution pattern may be specific to ethnic Chinese.
Strong linkage disequilibrium was observed between the MAOA-uVNTR and MAOA-CA markers because these two markers are only 24 Kb apart. The linkage disequilibrium D' value suggests only a negligible level of recombination in the population studied. The shorter MAOA-CA alleles were found most frequently on the chromosome carrying MAOA-uVNTR allele 4 or 5, whereas the longer MAOA-CA alleles appeared most frequently on the chromosome carrying MAOA-uVNTR allele 3 (data not shown). This result, however, is different from the previous report, in which strong linkage disequilibrium was observed for long MAOA-uVNTR with long MAOA-CA alleles and short MAOA-uVNTR with short MAOA-CA alleles in the U.S. population [18
]. The discrepancies in allelic distribution and phase of linkage disequilibrium might be attributable to ethnic differences.
In the past few years, our series studies focus on the association of serotonergic genes with BPD, including the serotonin synthetic enzymes TPH1 [31
] and TPH2 [33
], the serotonin transporter SLC6A4 [30
], and several serotonin receptors (HTRs) [32
]. Those results together with our findings in the current study support our hypothesis that the serotonergic system has a major impact on the pathogenesis of BPD. Although each of genes involved in the serotonergic system may contribute only a small to modest effect, their co-contribution with the environment or other genetic or epigenetic factors may result in BPD. Although our study suggested that MAOA might have a small effect on susceptibility to BPD, the chance of false positives cannot be excluded because of the sampling limitations (i.e., small sample size and subject assessment lacked support by structured interviews). Because of the limitations, further investigations with larger populations are required to elucidate the significance of MAOA on the pathogenesis of BPD in Taiwan.