Common Autism Genetic Polymorphisms Hidden in HLA and KIR Genes

Background:  Although there has been extensive research into the genetics of autism, only a small percentage of the genetic risk has been identified after studying thousands of subjects.  Genome wide association studies (GWAS) examining up to a million SNPs have detected rare variants in a small number of autism spectrum disorder (ASD) cases (under 10%). It has been suggested that rare variants are major contributor to genetic diseases and that autism involves the interaction of many rare variants. The extreme genetic heterogeneity of genes involved in both innate and adaptive immunity indicates that GWAS technology inadequately interrogates these complex gene families (Gourraud & et al., 2014, PLOS One, 9(7):e97282). We have, therefore, taken a more targeted approach to ASD genetic risk by examining human leukocyte antigens (HLA) and killer immunoglobulin-like receptor (KIR) genes (chromosomes 6 and 19 respectively), and have found several genetic associations that appear to fulfill the criteria of “common variants” for ASD.

Objectives:  To demonstrate unequivocally that specific HLA alleles and KIR gene content/haplotypes constitute important “common ASD variants” (greater than 5% differences between ASD and control populations).

Methods:  PCR-site specific primers (SSP) methodology is used to type HLA alleles and KIR genes from subjects and parents to determine inheritance and haplotypes. Standard statistical procedures are used for determining chi square, odds ratios, and meta-analysis.

Results:  We, and others have documented that genes in the HLA and KIR gene complexes are strongly associated with ASD.  The data, summarized in Table 1, documents that specific HLA alleles/haplotypes and KIR genes/haplotypes fulfill the “common variant criteria”.  For example, in three different population studies (P1-P3), the HLA-A2 allele is increased in the ASD subjects between 10.8 and 15.8% with odds ratios between 1.74 and 3.02.  Furthermore, the killer-cell activating gene alleles, KIR3DS1 and KIR2DS1, also are found in ASD subjects 15-22% more frequently than in normal controls.  Other HLA class I alleles (B7 and B15) and Class II alleles (DR15 and DR1104) are significantly more frequently found in ASD subjects, as are HLA extended haplotypes and KIR gene-content haplotypes (unpublished). Several alleles (A11 and DR7) and KIR haplotype CA01 are found less frequently in ASD subjects, suggesting that they may have a protective effect against ASD.

Conclusions: Our results suggest that HLA and KIR gene variants fulfill the criteria as common variant associations in ASD. These two immune gene complexes work together to modulate NK-cell killing with HLA as ligands for KIR receptors. The role that genes in the immune system play in the etiology of ASD is presently unclear but warrants further investigation.