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Allowing for sex differences increases power in a GWAS of multiplex Autism families

Molecular Psychiatry volume 17, pages 215–222 (2012)Cite this article

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Abstract

Current genomewide association studies account for only a small fraction of the estimated heritabilities of genetically complex neuropsychiatric disorders, indicating they are likely to result from the small effects of numerous predisposing variants, many of which have gone undetected. The statistical power to detect associations of common variants with small effects is increased by conducting joint association tests of a single nucleotide polymorphism (SNP), an additional risk factor (F), and their interaction. F can represent an environmental exposure, another genotype or any source of genetic heterogeneity. In case and control studies, logistic regression makes joint tests straightforward. This analytic method cannot be employed directly when SNP transmission tests are used to detect associations in parent/affected child trios and multiplex families. However, the method can be implemented using the case/pseudocontrol approach. We applied this approach to analyze data from a genomewide association study of multiplex families ascertained for Autism Spectrum Disorder, where sex was used to define the F. Joint analyses revealed two associations exceeding genomewide significance. One novel gene, Ryandine Receptor 2, implicated in calcium channel defects, was identified with a joint P-value of 3.9E−11. Calcium channel defects have been connected to Autism spectrum disorder (ASD) by Timothy Syndrome, which is Mendelian, and a previous targeted sex-specific association analysis of idiopathic Autism. A second gene, uridine phosphorylase 2, with a joint P-value of 2.3E−9, has been previously linked and associated with Autism in independent samples. These findings highlight two Autism candidate genes for follow-up studies.

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References

  1. Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ et al. Finding the missing heritability of complex diseases. Nature 2009; 461: 747–753.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Purcell SM, Wray NR, Stone JL, Visscher PM, O'Donovan MC, Sullivan PF et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 2009; 460: 748–752.

    CAS  PubMed  Google Scholar 

  3. Kraft P, Yen YC, Stram DO, Morrison J, Gauderman WJ . Exploiting gene-environment interaction to detect genetic associations. Hum Hered 2007; 63: 111–119.

    Article  CAS  PubMed  Google Scholar 

  4. Spielman RS, McGinnis RE, Ewens WJ . Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 1993; 52: 506–516.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Horvath S, Xu X, Laird NM . The family based association test method: strategies for studying general genotype—phenotype associations. Eur J Hum Genet 2001; 9: 301–306.

    Article  CAS  PubMed  Google Scholar 

  6. Cordell HJ, Barratt BJ, Clayton DG . Case/pseudocontrol analysis in genetic association studies: A unified framework for detection of genotype and haplotype associations, gene-gene and gene-environment interactions, and parent-of-origin effects. Genet Epidemiol 2004; 26: 167–185.

    Article  PubMed  Google Scholar 

  7. Cordell HJ, Clayton DG . A unified stepwise regression procedure for evaluating the relative effects of polymorphisms within a gene using case/control or family data: application to HLA in type 1 diabetes. Am J Hum Genet 2002; 70: 124–141.

    Article  CAS  PubMed  Google Scholar 

  8. Kanner L . The original description of autism, with excellent case examples. Nervous Child 1943; 2: 217–250.

    Google Scholar 

  9. Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E, Yuzda E et al. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med 1995; 25: 63–77.

    CAS  PubMed  Google Scholar 

  10. Abrahams BS, Geschwind DH . Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet 2008; 9: 341–355.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Weiss LA, Arking DE, Daly MJ, Chakravarti A . A genome-wide linkage and association scan reveals novel loci for autism. Nature 2009; 461: 802–808.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Szatmari P, Paterson AD, Zwaigenbaum L, Roberts W, Brian J, Liu XQ et al. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet 2007; 39: 319–328.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cantor RM . Molecular genetics of autism. Curr Psychiatry Rep 2009; 11: 137–142.

    Article  PubMed  Google Scholar 

  14. Autism and developmental disabilities monitoring network. 〈http://www.cdc.gov/mmwr/pdf/ss/ss5601.pef〉 2007.

  15. Yonan AL, Alarcon M, Cheng R, Magnusson PK, Spence SJ, Palmer AA et al. A genomewide screen of 345 families for autism-susceptibility loci. Am J Hum Genet 2003; 73: 886–897.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Stone JL, Merriman B, Cantor RM, Geschwind DH, Nelson SF . High density SNP association study of a major autism linkage region on chromosome 17. Hum Mol Genet 2007; 16: 704–715.

    Article  CAS  PubMed  Google Scholar 

  17. Cantor RM, Kono N, Duvall JA, Alvarez-Retuerto A, Stone JL, Alarcon M et al. Replication of autism linkage: fine-mapping peak at 17q21. Am J Hum Genet 2005; 76: 1050–1056.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Geschwind DH, Sowinski J, Lord C, Iversen P, Shestack J, Jones P et al. The autism genetic resource exchange: a resource for the study of autism and related neuropsychiatric conditions. Am J Hum Genet 2001; 69: 463–466.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Stone JL, Merriman B, Cantor RM, Yonan AL, Gilliam TC, Geschwind DH et al. Evidence for sex-specific risk alleles in autism spectrum disorder. Am J Hum Genet 2004; 75: 1117–1123.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Strom SP, Stone JL, Ten Bosch JR, Merriman B, Cantor RM, Geschwind DH et al. High-density SNP association study of the 17q21 chromosomal region linked to autism identifies CACNA1G as a novel candidate gene. Mol Psychiatry 2010; 15: 996–1005.

    Article  CAS  PubMed  Google Scholar 

  21. Lord C, Rutter M, Le Couteur A . Autism diagnostic interview-revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord 1994; 24: 659–685.

    Article  CAS  PubMed  Google Scholar 

  22. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–575.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. White H . A heteroskedasticity-consistent covariance matrix estimator and a direct test for heteroskedasticity. Econometrica 1980; 48: 817–830.

    Article  Google Scholar 

  24. Cordell HJ . Properties of case/pseudocontrol analysis for genetic association studies: Effects of recombination, ascertainment, and multiple affected offspring. Genet Epidemiol 2004; 26: 186–205.

    Article  PubMed  Google Scholar 

  25. Pe'er I, Yelensky R, Altshuler D, Daly MJ . Estimation of the multiple testing burden for genomewide association studies of nearly all common variants. Genet Epidemiol 2008; 32: 381–385.

    Article  PubMed  Google Scholar 

  26. Dudbridge F, Gusnanto A . Estimation of significance thresholds for genomewide association scans. Genet Epidemiol 2008; 32: 227–234.

    Article  PubMed  PubMed Central  Google Scholar 

  27. George CH, Higgs GV, Lai FA . Ryanodine receptor mutations associated with stress-induced ventricular tachycardia mediate increased calcium release in stimulated cardiomyocytes. Circ Res 2003; 93: 531–540.

    Article  CAS  PubMed  Google Scholar 

  28. Marks AR, Priori S, Memmi M, Kontula K, Laitinen PJ . Involvement of the cardiac ryanodine receptor/calcium release channel in catecholaminergic polymorphic ventricular tachycardia. J Cell Physiol 2002; 190: 1–6.

    Article  CAS  PubMed  Google Scholar 

  29. Cordell HJ . Estimation and testing of gene-environment interactions in family-based association studies. Genomics 2009; 93: 5–9.

    Article  CAS  PubMed  Google Scholar 

  30. Medeiros-Domingo A, Bhuiyan ZA, Tester DJ, Hofman N, Bikker H, van Tintelen JP et al. The RYR2-encoded ryanodine receptor/calcium release channel in patients diagnosed previously with either catecholaminergic polymorphic ventricular tachycardia or genotype negative, exercise-induced long QT syndrome: a comprehensive open reading frame mutational analysis. J Am Coll Cardiol 2009; 54: 2065–2074.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Priori SG, Napolitano C, Memmi M, Colombi B, Drago F, Gasparini M et al. Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia. Circulation 2002; 106: 69–74.

    Article  CAS  PubMed  Google Scholar 

  32. Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R et al. Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 2004; 119: 19–31.

    Article  CAS  PubMed  Google Scholar 

  33. Splawski I, Timothy KW, Decher N, Kumar P, Sachse FB, Beggs AH et al. Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations. Proc Natl Acad Sci USA 2005; 102: 8089–8096; discussion 8086-8088.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hemara-Wahanui A, Berjukow S, Hope CI, Dearden PK, Wu SB, Wilson-Wheeler J et al. A CACNA1F mutation identified in an X-linked retinal disorder shifts the voltage dependence of Cav1.4 channel activation. Proc Natl Acad Sci USA 2005; 102: 7553–7558.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Krey JF, Dolmetsch RE . Molecular mechanisms of autism: a possible role for Ca2+ signaling. Curr Opin Neurobiol 2007; 17: 112–119.

    Article  CAS  PubMed  Google Scholar 

  36. Palmieri L, Papaleo V, Porcelli V, Scarcia P, Gaita L, Sacco R et al. Altered calcium homeostasis in autism-spectrum disorders: evidence from biochemical and genetic studies of the mitochondrial aspartate/glutamate carrier AGC1. Mol Psychiatry 2010; 15: 38–52.

    Article  CAS  PubMed  Google Scholar 

  37. Alvarez Retuerto AI, Cantor RM, Gleeson JG, Ustaszewska A, Schackwitz WS, Pennacchio LA et al. Association of common variants in the Joubert syndrome gene (AHI1) with autism. Hum Mol Genet 2008; 17: 3887–3896.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Maestrini E, Pagnamenta AT, Lamb JA, Bacchelli E, Sykes NH, Sousa I et al. High-density SNP association study and copy number variation analysis of the AUTS1 and AUTS5 loci implicate the IMMP2L-DOCK4 gene region in autism susceptibility. Mol Psychiatry 2009; 15: 954–968.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Buxbaum JD, Silverman JM, Smith CJ, Kilifarski M, Reichert J, Hollander E et al. Evidence for a susceptibility gene for autism on chromosome 2 and for genetic heterogeneity. Am J Hum Genet 2001; 68: 1514–1520.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Shao Y, Raiford KL, Wolpert CM, Cope HA, Ravan SA, Ashley-Koch AA et al. Phenotypic homogeneity provides increased support for linkage on chromosome 2 in autistic disorder. Am J Hum Genet 2002; 70: 1058–1061.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. International Molecular Genetic Study of Autism Consortium (IMGSAC). A genomewide screen for autism: strong evidence for linkage to chromosomes 2q, 7q, and 16p. Am J Hum Genet 2001; 69: 570–581.

    Article  Google Scholar 

  42. Morrow EM, Yoo SY, Flavell SW, Kim TK, Lin Y, Hill RS et al. Identifying autism loci and genes by tracing recent shared ancestry. Science 2008; 321: 218–223.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Cantor RM, Lange K, Sinsheimer JS . Prioritizing GWAS results: A review of statistical methods and recommendations for their application. Am J Hum Genet 2010; 86: 6–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

These analyses were supported by NIH/NIMH Autism Center of Excellence network Grant MH081754 to Daniel Geschwind (PI). We gratefully acknowledge the resources provided by the Autism Genetic Resource Exchange (AGRE) Consortium and the participating AGRE families. The Autism Genetic Resource Exchange is a program of Autism Speaks and is supported, in part, by Grant 1U24MH081810 from the National Institute of Mental Health to Clara M. Lajonchere (PI).

The AGRE Consortium

Dan Geschwind, MD, PhD, UCLA, Los Angeles, CA; Maja Bucan, PhD, University of Pennsylvania, Philadelphia, PA; W Ted Brown, MD, PhD., FACMG, NYS Institute for Basic Research in Developmental Disabilities, Staten Island, NY; Rita M Cantor, PhD, UCLA School of Medicine, Los Angeles, CA; John N Constantino, MD, Washington University School of Medicine, St Louis, MO; T Conrad Gilliam, PhD, University of Chicago, Chicago, IL; Martha Herbert, MD, PhD, Harvard Medical School, Boston, MA Clara Lajonchere, PhD, Cure Autism Now, Los Angeles, CA; David H Ledbetter, PhD, Emory University, Atlanta, GA; Christa Lese-Martin, PhD, Emory University, Atlanta, GA; Janet Miller, JD, PhD, Cure Autism Now, Los Angeles, CA; Stanley F Nelson, MD, UCLA School of Medicine, Los Angeles, CA; Gerard D Schellenberg, PhD, University of Washington, Seattle, WA; Carol A Samango-Sprouse, EdD, George Washington University, Washington, DC; Sarah Spence, MD, PhD, UCLA, Los Angeles, CA; Matthew State, MD, PhD, Yale University, New Haven, CT. Rudolph E Tanzi, PhD, Massachusetts General Hospital, Boston, MA.

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Authors and Affiliations

  1. Department of Human Genetics, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA

    A T-H Lu & R M Cantor

  2. Department of Psychiatry, Center for Neurobehavioral Genetics, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA

    R M Cantor

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  1. A T-H Lu
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Correspondence to R M Cantor.

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Web Resources

AGRE, http://www.agre.org/index.cfm, Case/psedocontrol program available in dgc.genetics, an add-on package in R, http://www.r-project.org/, FBAT software, http://www.biostat.harvard.edu/~fbat/default.html, Haploview software, http://www.broad.mit.edu/mpg/haploview/, PLINK software, http://pngu.mgh.harvard.edu/~purcell/plink/dataman.shtml#extract, UCSC Genome Browser, http://genome.ucsc.edu/cgi-bin/hgGateway.

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Lu, AH., Cantor, R. Allowing for sex differences increases power in a GWAS of multiplex Autism families. Mol Psychiatry 17, 215–222 (2012). https://doi.org/10.1038/mp.2010.127

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