BAIAP2 exhibits association to childhood ADHD especially predominantly inattentive subtype in Chinese Han subjects

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder. The high heritability of approximately 0.76 [1] has suggested the important role of genetic factors in its etiology.

The typical development of human cerebral asymmetry has profound effect on the normal lateralization of cognitive and motor functions, such as language and handedness. Several studies have suggested the possible link of the disturbance of cerebral asymmetry with the pathogenesis of neurodevelopmental disorders [2], such as schizophrenia [3], autism [4] and ADHD [5].

The non-right-handedness, especially mixed-handedness, might be a risk indicator for the symptom severity of inattention in ADHD [6]. One of our previous behavioral studies indicated that ADHD children showed an atypical pattern of right hemisphere in conflict control task compared to controls [7]. Another study demonstrated that the direction of spatially asymmetrical interference effects in ADHD was opposite to controls, indicating disruption within right hemisphere attentional networks [8]. The structural imaging findings in ADHD has demonstrated volumetric reductions in total and right cerebral, right caudate, cerebellar and corpus callosum [9]. ADHD adults had thinner cortex in the cortical networks, especially in the right hemisphere involving inferior parietal lobule, dorsolateral prefrontal and anterior cingulate cortices [10]. In addition, some evidence has showed that the critical feature of ADHD is the delayed maturation not only of prefrontal cortical thickness but also of cortical surface area, especially the right hemispheric lobes [11, 12]. The degree of rightward volumetric asymmetry in caudate nucleus might predict the severity of inattentive symptoms of ADHD [13]. An fMRI study of ADHD children showed under-activation of the right caudate nucleus and inferior parieta cortex [14].

The gene BAIAP2, which is located on 17q25 and encodes brain-specific angiogenesis inhibitor 1-associated protein 2 (BAIAP2), has been suggested to be involved in cerebral asymmetry [15]. Recently, a genetic study of adulthood ADHD in two independent European populations suggested an association of BAIAP2 with ADHD, supplying genetic evidence of abnormal left-right brain asymmetries with this disorder [16]. In addition, a genome-wide association study (GWAS) has indicated nominal association between BAIAP2 and its isoform BAIAP2L1 with ADHD [17]. Moreover, methamphetamine, one of psychostimulants being considered as first-line pharmacological treatments for ADHD patients, has enhanced the expression of BAIAP2 in rat cerebral cortices [18]. BAIAP2 has also been found to confer risk for autism spectrum disorders (ASD), which shared some genetic risk factors with ADHD [19].

For the potentially important role of cerebral asymmetry in the pathophysiology of ADHD, BAIAP2 has been suggested to be one of novel candidate genes for ADHD, but need more work for replication [20]. Our present study is to investigate the relationship between BAIAP2 and ADHD in Chinese Han subjects.

Our results showed that BAIAP2 was associated with childhood ADHD of Chinese Han descent, especially for the predominantly inattentive type (ADHD-I). Analyses for case-control studies indicated different alleles and genotypes distribution between ADHD and controls, and the association was only retained for ADHD and ADHD-I after multiple corrections or adjusting the confounding effect of gender and age, but not for ADHD-C. From TDT tests for trios, the significant association was only indicated for ADHD-I from haplotype analyses.

In some extent, our current findings are consistant with previous reports. Ribasés et al. [16] have analyzed six functional candidate genes showing differential expression between hemispheres in ADHD and normal controls, but only found an association between BAIAP2 with ADHD. However, in their study, the association of BAIAP2 with ADHD was only observed in adults, which has also been replicated in an independent population, but not children. The possible explanation for this discrepancy may be that the genetic load for ADHD children may be lower than ADHD adults, while the sample size in the study by Ribasés et al. [16] may be not enough to detect the relatively weak association in ADHD children. Further investigation in ADHD adults of Chinese Han descent especially by follow-up studies may promote our understanding of the explicit effect of BAIAP2 on ADHD.

In our present study, the SNP rs4969385 was the only associated one with ADHD and ADHD-I after corrections for multiple testing. This SNP has also been reported in adult samples by Ribasés et al. [16]. This replication suggested further exploration of this SNP and its related functional variants in the predisposition to ADHD. However, we note that the direction of the effect in our current study was opposite to the one observed by Ribasés et al. [16]. In our study, the minor ‘T’ allele showed risk for ADHD, while the major ‘C’ allele did in Ribasés’s report. Previous studies has also reported similar phenomenon between different ethnicities [29, 30]. In addition, another SNP rs8079626, showing none association in our current study, has been reported to be of nominal association with adult ADHD in German sample by Ribasés et al. [16]. In their study, the ‘A’ allele showed higher frequencies in German adult ADHD sample than controls. In our study, for the ‘G’ allele, the transmission was more than non-transmission from TDT tests and its frequency was higher in ADHD probands versus controls, although not achieving statistically significant difference. When checking the LD between rs8079626 with the best two SNPs of our current analyses, we found its low LDs with rs3934492 (D’ = 0.231, r ²  = 0.04) and rs4969385 (D’ = 0.072, r ²  = 0.002). So we can conclude that the SNP rs8079626 was not associated with ADHD in Chinese Han subjects. This discrepancy may be greatly due to the ethnic difference, that its allele distribution in our current analyses of Chinese Han subjects (62.8% of G, 37.2% of A) was adverse to that of German samples (31.0% of G, 69.0% of A) from the study by Ribasés et al. [16]. This adverse distribution is according with the Hapmap database (62.2% of G for CHB, 28.3% of G for CEU). Taken together, it is very important to consider potential pathogenic genetic variants in different ethnic populations for ADHD etiological studies.

Another interesting finding is the specific association of BAIAP2 with ADHD-I subtype. Three subtypes of ADHD were defined in DSM-IV including predominantly inattentive, predominantly hyperactive/impulsive and the combined subtypes [31]. A growing body of literature has addressed that inattentive and combined subtypes may be distinct disorders [32, 33]. Attention-deficit disorder (ADD; inattentive, without hyperactivity) was different from ADHD on genetic basis, comorbidity, related brain region, etc. (for a review, see [33]). These findings have some effect on the revision of ADHD subtypes in DSM-V [34]. Our previous studies on molecular genetics have revealed the potential subtype-specific genes associated with ADHD in the Chinese Han population. COMT, 5-HT1B, MAOA, CHRNA4, SYP and DDC exhibited associations primarily with ADHD-I, whereas HTR2C, 5-HT1D, ADRA2C, DRD3 and NET1 were associated mainly with ADHD-C [24, 35–38]. The family-based study of NET1 and ADHD strongly suggested that the haplotype blocks within different regions of NET1 show divergent association based on sex and subtype [39]. Taken the current finding together with previous reports, considering subtypes in ADHD genetic studies is very important to reduce the heterogeneity and may help us to explore the hidden existed genes associated with ADHD.

Our findings need to be considered in light of some limitations. Firstly, twenty-seven genes have been identified involving in the left-right asymmetric cortical development in humans [15]. We only included BAIAP2 in this study and whether other genes played the role for the pathogenesis of ADHD remained unclear. Secondly, we have set MAF > 0.25 for tag SNPs selection and included an additional reported SNP rs4969385 with MAF of 0.162. We could not preclude the rare genetic contribution of uncommon SNPs (MAF <0.162) to the occurrence of ADHD. Thirdly, we have not screened those parents for ADHD diagnosis that we could not explain the genetic mechanisms of BAIAP2 in the etiology of ADHD clearly. Fourthly, ADHD was associated with high rates of comorbidity including dyslexia (reading disorder). In the existing literature, evidence has support the common risk neurobiological phenotype of atypical cerebral asymmetry (ACA) and shared ACA genes for ADHD and dyslexia [40]. The diagnosis instrument as described above in the present study lacked the ability to differ ADHD from dyslexia. Lastly, we did not collect data on the handedness, which is also strongly correlated with cerebral asymmetry. Then, we could not preclude the confounding effect of the diagnosis of dyslexia and handedness on our observed associations.

The present family-based and case-control association studies in our Chinese Han populations provide further evidence for the role of BAIAP2 in the predisposition to ADHD, especially ADHD-I. Further studies should investigate the involvement of hemispheric asymmetry genes modulating the difference of left-right hemisphere in ADHD and related cognition.