Risk Y-haplotypes and pathogenic variants of Arab-ancestry boys with autism by an exome-wide association study

• Published in: Molecular biology reports Vol. 47; no. 10; pp. 7623 - 7632
• Main Authors: Alsubaie, Laila M., Alsuwat, Hind Saleh, Almandil, Noor B, AlSulaiman, Abdulla, AbdulAzeez, Sayed, Borgio, J. Francis
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01-10-2020; Springer Nature B.V
• Subjects: Animal Anatomy; Animal Biochemistry; Arabs - genetics; Autism; Autistic children; Autistic Disorder - genetics; Biomedical and Life Sciences; Child; Child, Preschool; Chromosome deletion; Chromosomes, Human, Y - genetics; Genetic factors; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotyping; Haplotypes; Histology; Histones; Humans; Immune system; Life Sciences; Male; Mental disorders; Morphology; Neural coding; Neurodevelopmental disorders; Original Article; Pilot Projects; Polymorphism, Single Nucleotide; Risk Factors; Single-nucleotide polymorphism; Whole Exome Sequencing; Y chromosomes; SNPs; Y-chromosome; Haplotype; Boy; Autism spectrum disorder; Polymorphism
• ISSN: 0301-4851; 1573-4978
• DOI: 10.1007/s11033-020-05832-6

Autism is heterogeneous multifactorial neurodevelopmental and neuropsychiatric disorder with repetitive and limited behaviors as well as communication deficits. Prevalence of autism in males is predominant than females, but their genetic association is unclear. The study was performed to investigate Y-chromosome haplotypes, significant risk variants and susceptibility genes associated with autistic Saudi young males with autism. Exome genotyping microarray analysis was performed in Saudi young boys with autism (cases, n = 47) and without autism and other genetic or neurodevelopmental disorders (control, n = 43) to identify the functional exonic risk variations among 243,345 exonic variations. The most significant single nucleotide polymorphisms (SNPs) of protein coding associated with autism in Saudi young boys were studied for functional enrichment. Y-chromosome haplotyping analysis of 6 SNPs such as rs1865680, rs2032624, rs2032658, rs2032631, rs9786153 and rs13447352 uncovered the most significant protective (ACGACA
p
 = 2.94 × 10
−9
) among the controls and the high risk Y-haplotype (GAAGTC
p
 = 6.85 × 10
−6
) among autistic boys. Exome association study revealed 6 susceptible genes,
MCC, AUTS2, VSX1, SETBP1, CNTN3
, and
PCDH11Y
that were known for autistic disorder. The significant predisposed genes with functional variants of Y-chromomere are strongly connected with spermatogenic failure (
p
 = 8.02 × 10
−8
), azoospermia (
p
 = 6.32 × 10
−7
), partial chromosome Y deletion (
p
 = 7.66 × 10
−6
), HDMs demethylate histones pathway (
p
 = 3.55 × 10
−4
) and immune system diseases (
p
 = 4.11 × 10
−3
). Y-haplotypes and highly significant pathogenic exonic variants in
MCC, AUTS2, VSX1, SETBP1, CNTN3
and
PCDH11Y
genes are more influential genetic factors for developing autism in boys of Arab origin.