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

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Abstract

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.

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References

  1. Zoghbi HY, Bear MF (2012) Synaptic dysfunction in neurodevelopmental disorders associated with autism and intellectual disabilities. Cold Spring Harb Perspect Biol 4(3):a009886

    Article  PubMed Central  Google Scholar 

  2. Rylaarsdam LE, Guemez Gamboa A (2019) Genetic causes and modifiers in autism spectrum disorder. Front Cell Neurosci 13: 385

    Article  CAS  PubMed Central  Google Scholar 

  3. Almandil NB, Alkuroud DN, AbdulAzeez S, AlSulaiman A, Elaissari A, Borgio JF (2019) Environmental and genetic factors in autism spectrum disorders: special emphasis on data from Arabian studies. Int J Environ Res Public Health 16:658

    Article  CAS  Google Scholar 

  4. Al-Mubarak B, Abouelhoda M, Omar A, AlDhalaan H, Aldosari M et al (2017) Whole exome sequencing reveals inherited and de novo variants in autism spectrum disorder: a trio study from Saudi families. Sci Rep 7:1–4

    Article  CAS  Google Scholar 

  5. Alnemary FM, Aldhalaan HM, Simon-Cereijido G, Alnemary FM (2017) Services for children with autism in the Kingdom of Saudi Arabia. Autism 21:592–602

    Article  PubMed Central  Google Scholar 

  6. Al-Zahrani A (2013) Prevalence and clinical characteristics of autism spectrum disorders in school-age children in Taif-KSA. Int J Med Sci Public Health 2:578–582

    Article  Google Scholar 

  7. Dayem Ullah AZ, Lemoine NR, Chelala C (2012) SNPnexus: a web server for functional annotation of novel and publicly known genetic variants (2012 update). Nucl Acids Res 40(W1):W65–W70

    Article  CAS  PubMed Central  Google Scholar 

  8. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, De Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 8:559–575

    Article  Google Scholar 

  9. Barrett JC, Fry B, Maller JD, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265

    Article  CAS  PubMed Central  Google Scholar 

  10. Sherman BT, Lempicki RA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4:44

    Article  PubMed Central  Google Scholar 

  11. Szklarczyk D, Morris JH, Cook H, Kuhn M, Wyder S et al (2016) The STRING database in 2017: quality-controlled protein–protein association networks, made broadly accessible. Nucl Acids Res 18:gkw937

    Google Scholar 

  12. Kuleshov MV, Jones MR, Rouillard AD, Fernandez NF, Duan Q, Wang Z, Koplev S, Jenkins SL, Jagodnik KM, Lachmann A, McDermott MG (2016) Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucl Acids Res 44(W1):W90–W97

    Article  CAS  PubMed Central  Google Scholar 

  13. Chen J, Bardes EE, Aronow BJ, Jegga AG (2009) ToppGene Suite for gene list enrichment analysis and candidate gene prioritization. Nucl Acids Res 37:W305–W311

    Article  CAS  PubMed Central  Google Scholar 

  14. Quintana-Murci L, Fellous M (2001) The human Y chromosome: the biological role of a “functional wasteland”. Biomed Res Int 1:18–24

    CAS  Google Scholar 

  15. Turner ME, Ely D, Prokop J, Milsted A (2011) Sry, more than testis determination? Am J Physiol Regul Integr Comp Physiol 301:R561–R571

    Article  CAS  Google Scholar 

  16. Jobling MA, Tyler-Smith C (2000) New uses for new haplotypes: the human Y chromosome, disease and selection. Trends Genet 16:356–362

    Article  CAS  Google Scholar 

  17. Serajee FJ, Mahbubul Huq AHM (2009) Association of Y chromosome haplotypes with autism. J Child Neurol 24:1258–1261

    Article  Google Scholar 

  18. Jamain S, Quach H, Quintana-Murci L, Betancur C, Philippe A, Gillberg C et al (2002) Y chromosome haplogroups in autistic subjects. Mol Psychiatry 7:217–219

    Article  CAS  PubMed Central  Google Scholar 

  19. Weiner JA, Jontes J (2013) Protocadherins, not prototypical: a complex tale of their interactions, expression, and functions. Front Mol Neurosci 6:4

    PubMed  PubMed Central  Google Scholar 

  20. Priddle TH, Crow TJ (2013) The protocadherin 11X/Y (PCDH11X/Y) gene pair as determinant of cerebral asymmetry in modern Homo sapiens. Ann N Y Acad Sci 1288:36

    Article  CAS  PubMed Central  Google Scholar 

  21. Speevak MD, Farrell SA (2011) Non-syndromic language delay in a child with disruption in the Protocadherin11X/Y gene pair. Am J Med Genet B Neuropsychiatr Genet 156:484–489

    Article  CAS  Google Scholar 

  22. Blanco-Arias P, Sargent CA, Affara NA (2004) Protocadherin X (PCDHX) and Y (PCDHY) genes; multiple mRNA isoforms encoding variant signal peptides and cytoplasmic domains. Mammalian Genome 15:41–52

    Article  CAS  PubMed Central  Google Scholar 

  23. Kalscheuer VM, FitzPatrick D, Tommerup N, Bugge M, Niebuhr E, Neumann LM, Tzschach A, Shoichet SA, Menzel C, Erdogan F, Arkesteijn G (2007) Mutations in autism susceptibility candidate 2 (AUTS2) in patients with mental retardation. Hum Genet 121:501–509

    Article  PubMed Central  Google Scholar 

  24. Barnett CP, van Bon BWM (2015) Monogenic and chromosomal causes of isolated speech and language impairment. J Med Genet 52:719–729

    Article  CAS  PubMed Central  Google Scholar 

  25. Coe BP, Witherspoon K, Rosenfeld JA, Van Bon BW, Vulto-van Silfhout AT, Bosco P, Friend KL, Baker C, Buono S, Vissers LE, Schuurs-Hoeijmakers JH (2014) Refining analyses of copy number variation identifies specific genes associated with developmental delay. Nat Genet 46:1063

    Article  CAS  PubMed Central  Google Scholar 

  26. Monies D, Abouelhoda M, AlSayed M, Alhassnan Z, Alotaibi M, Kayyali H, Al-Owain M, Shah A, Rahbeeni Z, Al-Muhaizea MA, Alzaidan HI (2017) The landscape of genetic diseases in Saudi Arabia based on the first 1000 diagnostic panels and exomes. Hum Genet 136:921–939

    Article  CAS  PubMed Central  Google Scholar 

  27. Ye H, Liu J, Wu JY (2010) Cell adhesion molecules and their involvement in autism spectrum disorder. Neurosignals 18:62–71

    Article  CAS  PubMed Central  Google Scholar 

  28. AbdulAzeez S, Al Qahtani NH, Almandil NB, Al-Amodi AM, Aldakeel SA, Ghanem NZ et al (2019) Genetic disorder prenatal diagnosis and pregnancy termination practices among high consanguinity population, Saudi Arabia. Sci Rep 9:17248

    Article  PubMed Central  Google Scholar 

  29. Wolin SL, Belair C, Boccitto M, Chen X, Sim S, Taylor DW et al (2013) Non-coding Y RNAs as tethers and gates: insights from bacteria. RNA Biol 10:1602–1608

    Article  CAS  PubMed Central  Google Scholar 

  30. Scheckel C, Drapeau E, Frias MA, Park CY, Fak J, Zucker-Scharff I et al (2016) Regulatory consequences of neuronal ELAV-like protein binding to coding and non-coding RNAs in human brain. eLife 5:e10421

    Article  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank The Dean, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia for her continuous support and encouragement. We author appreciate the technical assistance from Mr. Ranilo M. Tumbaga, Mr. Horace T. Pacifico, and Ms. Jee E. Aquino.

Funding

This study was funded by by the Deanship of Scientific Research, Imam Abdulrahman Bin Faisal University (Grant No: 2016-057-IRMC, 2017-202-IRMC and 2018-094-IRMC).

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Authors and Affiliations

  1. Department of Genetic Research, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, Corniche Road, Dammam, Saudi Arabia

    Laila M. Alsubaie, Hind Saleh Alsuwat, Sayed AbdulAzeez & J. Francis Borgio

  2. Department of Biololgy, College of Science, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia

    Laila M. Alsubaie

  3. Department of Clinical Pharmacy Research, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia

    Noor B Almandil

  4. Department of Neurology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia

    Abdulla AlSulaiman

Authors
  1. Laila M. Alsubaie
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  2. Hind Saleh Alsuwat
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  3. Noor B Almandil
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  4. Abdulla AlSulaiman
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  5. Sayed AbdulAzeez
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  6. J. Francis Borgio
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Correspondence to J. Francis Borgio.

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The authors declare that they do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Electronic supplementary material 1 Analysis of Twelfths SNPs falls in the coding region of Ychromosome haplotypes (PDF 52 kb)

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Alsubaie, L.M., Alsuwat, H.S., Almandil, N.B. et al. Risk Y-haplotypes and pathogenic variants of Arab-ancestry boys with autism by an exome-wide association study. Mol Biol Rep 47, 7623–7632 (2020). https://doi.org/10.1007/s11033-020-05832-6

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  • DOI: https://doi.org/10.1007/s11033-020-05832-6

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