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Non-Mendelian etiologic factors in neuropsychiatric illness: Pleiotropy, epigenetics, and convergence

Published online by Cambridge University Press:  24 October 2012

Curtis K. Deutsch  and
William J. McIlvane
Curtis K. Deutsch
Affiliation:
Eunice Kennedy Shriver Center, University of Massachusetts Medical School, Waltham, MA 02452. curtis.deutsch@umassmed.edu william.mcilvane@umassmed.edu
William J. McIlvane
Affiliation:
Eunice Kennedy Shriver Center, University of Massachusetts Medical School, Waltham, MA 02452. curtis.deutsch@umassmed.edu william.mcilvane@umassmed.edu
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Abstract

The target article by Charney on behavior genetics/genomics discusses how numerous molecular factors can inform heritability estimations and genetic association studies. These factors find application in the search for genes for behavioral phenotypes, including neuropsychiatric disorders. We elaborate upon how single causal factors can generate multiple phenotypes, and discuss how multiple causal factors may converge on common neurodevelopmental mechanisms.

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Type
Open Peer Commentary
Information
Behavioral and Brain Sciences , Volume 35 , Issue 5 , October 2012 , pp. 363 - 364
Copyright
Copyright © Cambridge University Press 2012 

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References

Basoglu, C., Oner, O., Ates, A., Algul, A., Bez, Y. Cetin, M., Herken, H., Erdal, M. E. & Munir, K. M. (2011) Synaptosomal-associated protein 25 gene polymorphisms and antisocial personality disorder: Association with temperament and psychopathy. Canadian Journal of Psychiatry 56(6):341–47.CrossRefGoogle ScholarPubMed
Bijlsma, E. K., Gijsbers, A. C., Schuurs-Hoeijmakers, J. H., van Haeringen, A., Fransen van de Putte, D. E., Anderlid, B. M., Lundin, J., Lapunzina, P., Pérez Jurado, L. A., Delle Chiaie, B., Loeys, B., Menten, B., Oostra, A., Verhelst, H., Amor, D. J., Bruno, D. L., van Essen, A. J., Hordijk, R., Sikkema-Raddatz, B., Verbruggen, K. T., Jongmans, M. C., Pfundt, R., Reeser, H. M., Breuning, M. H. & Ruivenkamp, C. A. (2009) Extending the phenotype of recurrent rearrangements of 16p11.2: Deletions in mentally retarded patients without autism and in normal individuals. European Journal of Medical Genetics 52(2–3):77–87. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19306953.CrossRefGoogle ScholarPubMed
Cichon, S., Craddock, N., Daly, M., Faraone, S. V., Gejman, P. V., Kelsoe, J., Lehner, T., Levinson, D. F., Moran, A., Sklar, P. & Sullivan, P. F. (2009) Genomewide association studies: history, rationale, and prospects for psychiatric disorders. American Journal of Psychiatry 166(5): 540–56. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19339359.Google ScholarPubMed
Deutsch, C. K., Ludwig, W. W. & McIlvane, W. J. (2008) Heterogeneity and hypothesis testing in neuropsychiatric illness. Behavioral and Brain Sciences 31(3):266–67. Available at: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18578910.CrossRefGoogle ScholarPubMed
Gejman, P. V., Sanders, A. R. & Kendler, K. S. (2011) Genetics of schizophrenia: New findings and challenges. Annual Review of Genomics Human Genetics 12:121–44. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21639796 CrossRefGoogle Scholar
Holzman, P. S., Kringlen, E., Matthysse, S., Flanagan, S. D., Lipton, R. B., Cramer, G. Levin, S., Lange, K. & Levy, D. L. (1988) A single dominant gene can account for eye tracking dysfunctions and schizophrenia in offspring of discordant twins. Archives of General Psychiatry 45(7):641–47. Available at: http://www.ncbi.nlm.nih.gov/pubmed?term=A%20single%20dominant%20gene%20can%20account%20for%20eye%20tracking%20dysfunctions%20and%20schizophrenia%20in%20offspring%20of%20discordant%20twins.%20Archives%20of%20General%20Psychiatry%2C%2045(7) CrossRefGoogle ScholarPubMed
Kendler, K. S., Kalsi, G., Holmans, P. A., Sanders, A. R., Aggen, S. H., Dick, D. M., Aliev, F., Shi, J., Levinson, D. F. & Gejman, P. V. (2011) Genomewide association analysis of symptoms of alcohol dependence in the molecular genetics of schizophrenia (MGS2) control sample. Alcoholism, clinical and experimental research 35(5): 963–75. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21314694.CrossRefGoogle ScholarPubMed
Lionel, A. C., Crosbie, J., Barbosa, N., Goodale, T., Thiruvahindrapuram, B., Rickaby, J., Gazzellone, M., Carson, A. R., Howe, J. L., Wang, Z., Wei, J., Stewart, A. F., Roberts, R., McPherson, R., Fiebig, A., Franke, A., Schreiber, S., Zwaigenbaum, L., Fernandez, B. A., Roberts, W., Arnold, P. D., Szatmari, P., Marshall, C. R., Schachar, R. & Scherer, S. W. (2011) Rare copy number variation discovery and cross-disorder comparisons identify risk genes for ADHD. Science Translational Medicine 3(95): 95ra75. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21832240.CrossRefGoogle ScholarPubMed
Matthysse, S., Holzman, P. S., Gusella, J. F., Levy, D. L., Harte, C. B., Jorgensen, A., Moller, L. & Parnas, J. (2004) Linkage of eye movement dysfunction to chromosome 6p in schizophrenia: Additional evidence. American Journal of Medical Genetics B Neuropsychiatric Genetics 128B(1):30–36.CrossRefGoogle ScholarPubMed
McCarthy, S. E., Makarov, V., Kirov, G., Addington, A. M., McClellan, J., Yoon, S., Perkins, D. O., Dickel, D. E., Kusenda, M., Krastoshevsky, O., Krause, V., Kumar, R. A., Grozeva, D., Malhotra, D., Walsh, T., Zackai, E. H., Kaplan, P., Ganesh, J., Krantz, I. D., Spinner, N. B., Roccanova, P., Bhandari, A., Pavon, K., Lakshmi, B., Leotta, A., Kendall, J., Lee, Y. H., Vacic, V., Gary, S., Iakoucheva, L. M., Crow, T. J., Christian, S. L., Lieberman, J. A., Stroup, T. S., Lehtimaki, T., Puura, K., Haldeman-Englert, C., Pearl, J., Goodell, M., Willour, V. L., Derosse, P., Steele, J., Kassem, L., Wolff, J., Chitkara, N., McMahon, F. J., Malhotra, A. K., Potash, J. B., Schulze, T. G., Nothen, M. M., Cichon, S., Rietschel, M., Leibenluft, E., Kustanovich, V., Lajonchere, C. M., Sutcliffe, J. S., Skuse, D., Gill, M., Gallagher, L., Mendell, N. R., Craddock, N., Owen, M. J., O'Donovan, M. C., Shaikh, T. H., Susser, E., Delisi, L. E., Sullivan, P. F., Deutsch, C. K., Rapoport, J., Levy, D. L., King, M. C. & Sebat, J. (2009) Microduplications of 16p11.2 are associated with schizophrenia. Nature Genetics 41(11): 1223–27. Available at: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19855392.CrossRefGoogle ScholarPubMed
Mefford, H. C., Batshaw, M. L. & Hoffman, E. P. (2012) Genomics, intellectual disability, and autism [Review]. New England Journal of Medicine 366(8):733–43. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22356326.CrossRefGoogle ScholarPubMed
Nadeau, J. H. & Topol, E. J. (2006) The genetics of health. Nature Genetics 38(10):1095–98. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17006459.CrossRefGoogle ScholarPubMed
Neale, B. M., Kou, Y., Liu, L., Ma'ayan, A., Samocha, K. E., Sabo, A., Lin, C. F., Stevens, C., Wang, L. S., Makarov, V., Polak, P., Yoon, S., Maguire, J., Crawford, E. L., Campbell, N. G., Geller, E. T., Valladares, O., Schafer, C., Liu, H., Zhao, T., Cai, G., Lihm, J., Dannenfelser, R., Jabado, O., Peralta, Z., Nagaswamy, U., Muzny, D., Reid, J. G., Newsham, I., Wu, Y., Lewis, L., Han, Y., Voight, B. F., Lim, E., Rossin, E., Kirby, A., Flannick, J., Fromer, M., Shakir, K., Fennell, T., Garimella, K., Banks, E., Poplin, R., Gabriel, S., Depristo, M., Wimbish, J. R., Boone, B. E., Levy, S. E., Betancur, C., Sunyaev, S., Boerwinkle, E., Buxbaum, J. D., Cook, E. H., Devlin, B., Gibbs, R. A., Roeder, K., Schellenberg, G. D., Sutcliffe, J. S. & Daly, M. J. (2012) Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485(7397):242–45. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22495311.CrossRefGoogle ScholarPubMed
O'Roak, B. J., Deriziotis, P., Lee, C., Vives, L., Schwartz, J. J., Girirajan, S., Karakoc, E., Mackenzie, A. P., Ng, S. B., Baker, C., Rieder, M. J., Nickerson, D. A., Bernier, R., Fisher, S. E., Shendure, J. & Eichler, E. E. (2012a) Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nature Genetics 44(4): 471.CrossRefGoogle Scholar
O'Roak, B. J., Vives, L., Girirajan, S., Karakoc, E., Krumm, N., Coe, B. P., Levy, R., Ko, A., Lee, C., Smith, J. D., Turner, E. H., Stanaway, I. B., Vernot, B., Malig, M., Baker, C., Reilly, B., Akey, J. M., Borenstein, E., Rieder, M. J., Nickerson, D. A., Bernier, R., Shendure, J. & Eichler, E. E. (2012b) Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485(7397):246–50. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22495309.CrossRefGoogle ScholarPubMed
Poot, M., van der Smagt, J. J., Brilstra, E. H. & Bourgeron, T. (2011) Disentangling the myriad genomics of complex disorders, specifically focusing on autism, epilepsy, and schizophrenia [Review]. Cytogenetic and Genome Research 135(3–4):228–40. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22085975.CrossRefGoogle Scholar
Psychiatric GWAS Consortium Coordinating Committee (2009) Genomewide association studies: History, rationale, and prospects for psychiatric disorders. American Journal of Psychiatry 166(5):540–56.CrossRefGoogle Scholar
Sanders, S. J., Murtha, M. T., Gupta, A. R., Murdoch, J. D., Raubeson, M. J., Willsey, A. J., Ercan-Sencicek, A. G., Dilullo, N. M., Parikshak, N. N., Stein, J. L., Walker, M. F., Ober, G. T., Teran, N. A., Song, Y., El-Fishawy, P., Murtha, R. C., Choi, M., Overton, J. D., Bjornson, R. D., Carriero, N. J., Meyer, K. A., Bilguvar, K., Mane, S. M., Sestan, N., Lifton, R. P., Gunel, M., Roeder, K., Geschwind, D. H., Devlin, B. & State, M. W. (2012) De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485(7397):237–41. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22495306.CrossRefGoogle ScholarPubMed
Shulha, H. P., Cheung, I., Whittle, C., Wang, J., Virgil, D., Lin, C. L., Guo, Y., Lessard, A., Akbarian, S. & Weng, Z. (2012) Epigenetic signatures of: Trimethylated H3K4 landscapes in prefrontal neurons. Archives of General Psychiatry 69(3): 314–24.CrossRefGoogle ScholarPubMed
Sunga, H., Ji, F., Levy, D. L., Matthysse, S. & Mendell, N. R. (2009) The power of linkage analysis of a disease-related endophenotype using asymmetrically ascertained sib pairs. Computational Statistics & Data Analysis 53(5):1829–42. http://www.ncbi.nlm.nih.gov/pubmed/20160849 CrossRefGoogle Scholar
Voineagu, I., Wang, X., Johnston, P., Lowe, J. K., Tian, Y., Horvath, S. & ., Mill, J., Cantor, R. M., Blencowe, B. J. & Geschwind, D. H. (2011) Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature 474(7351): 380–84. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21614001 CrossRefGoogle ScholarPubMed
Weber, H., Kittel-Schneider, S., Gessner, A., Domschke, K., Neuner, M., Jacob, C. P., Buttenschon, H. N., Boreatti-Hummer, A., Volkert, J., Herterich, S., Baune, B. T., Gross-Lesch, S., Kopf, J., Kreiker, S., Nguyen, T. T., Weissflog, L., Arolt, V., Mors, O., Deckert, J., Lesch, K. P. & Reif, A. (2011) Cross-disorder analysis of bipolar risk genes: Further evidence of DGKH as a risk gene for bipolar disorder, but also unipolar depression and adult ADHD. Neuropsychopharmacology 36(10): 2076–85.CrossRefGoogle ScholarPubMed
Yeo, G. S. (2011) Where next for GWAS? [Editorial Introductory]. Briefings in Functional Genomics 10(2): 51.CrossRefGoogle ScholarPubMed