This family-based association study was performed in 640 Han Chinese autism trios to investigate the relationships between two SNPs (rs1344706 and rs7603001) in ZNF804A and autism. Our results indicated that these two SNPs were not associated with autism in a Han Chinese population.
Our findings were inconsistent with those of a previous study. Using data of 841 autistic families from AGRE, Anitha et al. found that rs7603001 in
ZNF804A was nominally associated with autism (
P = 0.018), especially in the subgroup of autistic individuals with verbal deficit (
P = 0.008). Another SNP, rs1344706, which was frequently reported in SCZ, showed no association with autism [
15]. In addition, no association of rs1344706 (OR for A allele = 0.9805,
P = 0.1597) or rs7603001 (OR for A allele = 0.9848,
P = 0.2666) was found using genome-wide association data from the Integrative Psychiatric Research and the Psychiatric Genomics Consortium released in 2017 (iPSYCH-PGC GWAS 2017, available at:
http://www.med.unc.edu/pgc/results-and-downloads), which included data of 18,381 autistic individuals and 27,969 controls [
40].
Although this study detected no association between
ZNF804A and autism, certain factors should be considered for further studies. First, autism is a complex heterogeneous disorder. Susceptibility genes might contribute to different subgroups of autism [
41‐
45]. Concerning
ZNF804A, a nominal association was detected between rs7603001 and autism, especially in autism individuals with verbal deficit. Hence, the relationship between candidate genes and specific phenotypes of autism should be further explored. Second, other SNPs or structural abnormalities such as copy number variations (CNVs) in
ZNF804A might be involved in the etiology of autism. In the dataset of iPSYCH-PGC GWAS 2017, a few SNPs, including rs146362735, rs114385979, and rs77076543, were nominally associated with ASD (
P < 0.01). However, these SNPs showed no polymorphism in the CHB population. Recently, one study found that rs10497655 in
ZNF804A was significantly associated with ASD (OR = 1.20 (95%CI 1.05–1.37),
P = 0.007851) in a Han Chinese cohort (854 cases and 926 controls) and the T risk allele homozygotes of rs10497655 could reduce
ZNF804A expression [
46]. On the other hand, Griswold et al. found duplications of CNVs in
ZNF804A only in autistic individuals [
47]. In another study, an excess of CNVs in
ZNF804A was detected in 19,556 patients with neurodevelopmental disorders compared with 13,991 controls (
P = 0.047) [
48]. Therefore, the association between autism and other SNPs, and/or structural abnormalities in
ZNF804A should be further investigated. Third, differences in ethnic genetic background might contribute to the result inconsistencies. For instance, r
2 between rs1344706 and rs7603001 were 0.637, 0.232 and 0.353 in CEU (Utah residents with Northern and Western European ancestry from the CEPH collection), CHB and JPT (Japanese in Tokyo), respectively (Additional file
1: Figure S1). Besides, rs1344706 was reported to confer risk of SCZ in the European populations. However, a meta-analysis study found only nominal association between this variant and SCZ in the Asian population (13,452 cases, 17,826 healthy controls, and 680 families). No association was showed between rs1344706 and SCZ in samples from the Chinese population [
49]. Association studies in other populations are required to assess the involvement of
ZNF804A in autism. Fourth, the present sample size was limited. More autism patients and families of Han Chinese ancestry need to be involved in further researches to increase the statistical power and might help indicate new susceptibility variants.