Incorporating information from markers in LD with test locus for detecting imprinting and maternal effects

Abstract

Numerous statistical methods have been developed to explore genomic imprinting and maternal effects by identifying parent-of-origin patterns in complex human diseases. However, because most of these methods only use available locus-specific genotype data, it is sometimes impossible for them to infer the distribution of parental origin of a variant allele, especially when some genotypes are missing. In this article, we propose a two-step approach, LIMEhap, to improve upon a recent partial likelihood inference method. In the first step, the distribution of the missing genotypes is inferred through the construction of haplotypes by using information from nearby loci. In the second step, a partial likelihood method is applied to the inferred data. To substantiate the validity of the proposed procedures, we simulated data in a genomic region of gene GPX1. The results show that, by borrowing genetic information from nearby loci, the power of the proposed method can be close to that with complete genotype data at the locus of interest. Since the inference on the genotype distribution is made under the assumption of Hardy–Weinberg Equilibrium (HWE), we further studied the robustness of LIMEhap to violation of HWE. Finally, we demonstrate the utility of LIMEhap by applying it to an autism dataset.

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Fig. 1: Type I error and power for eight disease models (labeled 1–8 corresponding to the numbering in Table 2) for the scenario in which HWE does not hold and PREV = 0.05.
Fig. 2: Power for imprinting effect at different test locus when HWE holds and PREV = 0.05.

References

  1. 1.

    Lawson HA, Cheverud JM, Wolf JB. Genomic imprinting and parent-of-origin effects on complex traits. Nat Rev Genet. 2013;14:609–17.

  2. 2.

    Nousome D, Lupo PJ, Okcu MF, Scheurer ME. Maternal and offspring xenobiotic metabolism haplotypes and the risk of childhood acute lymphoblastic leukemia. Leuk Res. 2013;37:531–5.

  3. 3.

    Ferguson-Smith AC. Genome imprinting: the emergence of an epigenetic paradigm. Nat Rev. 2011;12:565–75.

  4. 4.

    Naumova AK, Croteau S. Mechanisms of epigenetic variation: polymorphic imprinting. Curr Genomics. 2004;5:417–29.

  5. 5.

    Hager R, Cheverud JM, Wolf JB. Maternal effects as the cause of parent-of-origin effects that mimic genomic imprinting. Genetics. 2008;178:1755–62.

  6. 6.

    Lin S. Assessing the effects of imprinting and maternal genotypes on complex genetic traits. In: Lee M-LT, Gail M, Pfeiffer R, Satten G, Cai T, Gandy A, editors. Risk assessment and evaluation of predictions. New York, NY, USA: Springer; 2013. p. 285–300.

  7. 7.

    Weinberg CR, Wilcox AJ, Lie RT. A log-linear approach to case-parent-triad data: assessing effects of disease genes that act either directly or through maternal effects and that may be subject to parental imprinting. Am J Hum Genet. 1998;62:969–78.

  8. 8.

    Weinberg CR. Methods for detection of parent-of-origin effects in genetic studies of case-parents triads. Am J Hum Genet. 1999;65:229–35.

  9. 9.

    Ainsworth HF, Unwin J, Jamison DL, Cordell HJ. Investigation of maternal effects, maternal-fetal interactions and parent-of-origin effects (imprinting), using mothers and their offspring. Genet Epidemiol. 2011;35:19–45.

  10. 10.

    Shi M, Umbach DM, Vermeulen SH, Weinberg CR. Making the most of case-mother/control-mother studies. Am J Epidemiol. 2008;168:541–7.

  11. 11.

    Yang J, Lin S. Robust partial likelihood approach for detecting imprinting and maternal effects using case-control families. Ann Stat. 2013;7:249–68.

  12. 12.

    Kong A, Steinthorsdottir V, Masson G, Thorleifsson G, Sulem P, Besenbacher S, et al. Parental origin of sequence variants associated with complex diseases. Nature. 2009;462:868–74.

  13. 13.

    Lin D, Weinberg CR, Feng R, Hochner H, Chen J. A multi-locus likelihood method for assessing parent-of-origin effects using case-control mother–child pairs. Genet Epidemiol. 2013;37:152–62.

  14. 14.

    Howey R, Mamasoula C, Töpf A, Nudel R, Goodship JA, Keavney BD, et al. Increased power for detection of parent-of-origin effects via the use of haplotype estimation. Am J Hum Genet. 2015;97:419–34.

  15. 15.

    Zhang K, Sun F, Zhao H. HAPLORE: a program for haplotype reconstruction in general pedigrees without recombination. Bioinformatics. 2005;21:90–103.

  16. 16.

    Chen J, Peters U, Foster C, Chatterjee N. A haplotype based test of association using data from cohort and nested case-control epidemiologic studies. Hum Hered. 2004;58:18–29.

  17. 17.

    Chen J, Chatterjee N. Haplotype based association analysis in cohort and nested case-control studies. Biometrics. 2006;62:28–35.

  18. 18.

    Weir BS. Genetic data analysis II. Sunderland, MA, USA: Sinauer; 1996.

  19. 19.

    Lahiri DK, Sokol DK, Erickson C, Ray B, Ho CY, Maloney B. Autism as early neurodevelopmental disorder: evidence for an sAPPα-mediated anabolic pathway. Front Cell Neurosci. 2013;7:94.

  20. 20.

    Xiao Z, Qiu T, Ke X, Xiao X, Xiao T, Liang F, et al. Autism spectrum disorder as early neurodevelopmental disorder: evidence from the brain imaging abnormalities in 2-3 years old toddlers. J Autism Dev Disord. 2014;44:1633–40.

  21. 21.

    Sandin S, Lichtenstein P, Kuja-Halkola R, Hultman C, Larsson H, Reichenberg A. The heritability of autism spectrum disorder. JAMA. 2017;318:1182–4.

  22. 22.

    Tick B, Bolton P, Happé F, Rutter M, Rijsdijk F. Heritability of autism spectrum disorders: a meta-analysis of twin studies. J Child Psychol Psychiatry. 2016;57:585–95.

  23. 23.

    Fradin D, Cheslack-Postava K, Ladd-Acosta C, Newschaffer C, Chakravarti A, Arking DE, et al. Parent-of-origin effects in autism identified through genome-wide linkage analysis of 16,000 SNPs. PLoS ONE. 2010;5:e12513.

  24. 24.

    Loke YJ, Hannan AJ, Craig JM. The role of epigenetic change in autism spectrum disorders. Front Neurol. 2015;6:107.

  25. 25.

    Porokhovnik LN, Kostyuk SV, Ershova ES, Stukalov SM, Veiko NN, Korovina NY, et al. The maternal effect in infantile autism: elevated DNA damage degree in patients and their mothers. Biomed Khim. 2016;62:466–70.

  26. 26.

    Cheng Y, Quinn JF, Weiss LA. An eQTL mapping approach reveals that rare variants in the SEMA5A regulatory network impact autism risk. Hum Mol Genet. 2013;22:2960–72.

  27. 27.

    Zhang F, Khalili A, Lin S. Optimum study design for detecting imprinting and maternal effects based on partial likelihood. Biometrics. 2016;72:95–105.

  28. 28.

    Ruser TF, Arin D, Dowd M, Putnam S, Winklosky B, Rosen-Sheidley B, et al. Communicative competence in parents of children with autism and parents of children with specific language impairment. J Autism Dev Disord. 2007;37:1323–36.

  29. 29.

    Pinto D, Delaby E, Merico D, Barbosa M, Merikangas A, Klei L, et al. Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. Am J Hum Genet. 2014;94:677–94.

  30. 30.

    Li H, Li Y, Shao J, Li R, Qin Y, Xie C, et al. The association analysis of RELN and GRM8 genes with autistic spectrum disorder in Chinese Han population. Am J Med Genet. 2008;B 147:194–200.

  31. 31.

    Salyakina D, Cukier HN, Lee JM, Sacharow S, Nations LD, Ma D, et al. Copy number variants in extended autism spectrum disorder families reveal candidates potentially involved in autism risk. PLoS One. 2011;6:e26049–e26049.

  32. 32.

    Suda S, Iwata K, Shimmura C, Kameno Y, Anitha A, Thanseem I, et al. Decreased expression of axon-guidance receptors in the anterior cingulate cortex in autism. Mol Autism. 2011;2:14–14.

  33. 33.

    Fenster SD, Garner CC. Gene structure and genetic localization of the PCLO gene encoding the presynaptic active zone protein Piccolo. Int J Neurosci. 2002;20:161–71.

  34. 34.

    Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, Walsh T, et al. Strong association of de novo copy number mutations with autism. Science. 2007;316:445–9.

  35. 35.

    Kong A, Masson G, Frigge ML, Gylfason A, Zusmanovich P, Thorleifsson G, et al. Detection of sharing by descent, long-range phasing and haplotype imputation. Nat Genet. 2008;40:1068–75.

  36. 36.

    Zhang F, Khalili A, Lin S. Imprinting and maternal effect detection using partial likelihood based on discordant sibpair data. Stat Sin. 2019;29:1915–37.

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Acknowledgements

The authors would like to thank the Section Editor and the anonymous reviewers for their constructive comments and suggestions, which, in our view, have led to improved presentation and greater clarity. The autism spectrum disorder family data, made available by the AGP, were downloaded from dbGaP (Accession: phs000267.v1.p1).

Funding

This work was supported in part by the National Science Foundation grant DMS-1208968.

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Correspondence to Shili Lin.

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Zhang, F., Lin, S. Incorporating information from markers in LD with test locus for detecting imprinting and maternal effects. Eur J Hum Genet (2020). https://doi.org/10.1038/s41431-020-0590-3

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