Pleiotropy

This signifies multiple manifestations stemming from a single causal factor. Take, for example, the effects of the phosphatase and tensin homolog (PTEN) gene, located at 10q23.31. It encodes a tumor suppressor phosphatase that antagonizes the PI3K signaling pathway, which contributes to a variety of conditions. These include specific clinical genetic syndromes (e.g., Bannayan-Riley-Ruvalcaba), macrocephaly, autism, and malignant melanoma (Nadeau & Topol Reference Nadeau and Topol2006). These multiple manifestations are conceptually unified when the underlying mechanism is revealed.

A single etiologic factor can have multiple phenotypes, present in some but not all gene carriers. This genetic heterogeneity, combined with reduced penetrance for a diagnosis, may increase the risk of false negatives in gene discovery; the power to detect linkage on the basis of the disease phenotype alone is limited. Thus, there is a potential boon in studying not only the psychiatric illness, but also alternative phenotypes that provide a more complete picture of pleiotropic manifestations.

There can be marked statistical power benefits to this pleiotropic approach (Sunga et al. Reference Sunga, Ji, Levy, Matthysse and Mendell2009). For example, in schizophrenia, common underlying causal factor(s) may generate not only the clinical diagnosis, but also eye movement disorders, which are present in the majority of schizophrenia patients (Holzman et al. Reference Holzman, Kringlen, Matthysse, Flanagan, Lipton, Cramer, Levin, Lange and Levy1988). Matthysse et al. (Reference Matthysse, Holzman, Gusella, Levy, Harte, Jorgensen, Moller and Parnas2004) modeled the cotransmission of both phenotypes, schizophrenia and eye movement disorders, among probands and their relatives, yielding a linkage analysis that identified a locus on chromosome 6.

Copy number variants (CNVs)

Recent genetic studies have heralded the importance of genetic CNVs in brain-based disorders, as Charney describes. Pleiotropy is increasingly discussed with respect to CNVs (e.g., Poot et al. Reference Poot, van der Smagt, Brilstra and Bourgeron2011), and single microdeletions and microduplications have been found to have a variety of manifestations. For example, a cluster of rare disorder-associated CNVs on chromosome 9 (containing the microdeletion 9q33.1, which includes neurodevelopmental genes astrotactin 2 [ASTN2] and tripartite motif-containing 32 [TRIM32]) has been associated with a variety of conditions: bipolar disorder, schizophrenia, and autism spectrum disorder (ASD; Lionel et al. Reference Lionel, Crosbie, Barbosa, Goodale, Thiruvahindrapuram, Rickaby, Gazzellone, Carson, Howe, Wang, Wei, Stewart, Roberts, McPherson, Fiebig, Franke, Schreiber, Zwaigenbaum, Fernandez, Roberts, Arnold, Szatmari, Marshall, Schachar and Scherer2011). A similar phenomenon exists for the microdeletion of 16p11.2, observed in ASD (McCarthy et al. Reference McCarthy, Makarov, Kirov, Addington, McClellan, Yoon, Perkins, Dickel, Kusenda, Krastoshevsky, Krause, Kumar, Grozeva, Malhotra, Walsh, Zackai, Kaplan, Ganesh, Krantz, Spinner, Roccanova, Bhandari, Pavon, Lakshmi, Leotta, Kendall, Lee, Vacic, Gary, Iakoucheva, Crow, Christian, Lieberman, Stroup, Lehtimaki, Puura, Haldeman-Englert, Pearl, Goodell, Willour, Derosse, Steele, Kassem, Wolff, Chitkara, McMahon, Malhotra, Potash, Schulze, Nothen, Cichon, Rietschel, Leibenluft, Kustanovich, Lajonchere, Sutcliffe, Skuse, Gill, Gallagher, Mendell, Craddock, Owen, O'Donovan, Shaikh, Susser, Delisi, Sullivan, Deutsch, Rapoport, Levy, King and Sebat2009); the same CNV is also seen among individuals with intellectual disability in the absence of ASD (Bijlsma et al. Reference Bijlsma, Gijsbers, Schuurs-Hoeijmakers, van Haeringen, Fransen van de Putte, Anderlid, Lundin, Lapunzina, Pérez Jurado, Delle Chiaie, Loeys, Menten, Oostra, Verhelst, Amor, Bruno, van Essen, Hordijk, Sikkema-Raddatz, Verbruggen, Jongmans, Pfundt, Reeser, Breuning and Ruivenkamp2009). The association of both intellectual disability and psychiatric illness with a single CNV is seen for a number of other novel recurrent copy number changes, including 1q21.1 deletion and duplication, 3q29 deletion, 15q11.2 deletion, 15q13.3 deletion, 15q24 deletion, 16p13.11 deletion and duplication, and 17q12 deletion (Mefford et al. Reference Mefford, Batshaw and Hoffman2012).

Single genes

A limitation to gene discovery in CNVs is the sheer magnitude of genetic material within many deleted or duplicated regions; yet the chief pathogenic genes may isolated to a small subset of this region. Without a comprehensive genetic dissection of the region, strong inference about associations with phenotypes is impossible. A more direct approach is to delineate genotype-phenotype relationships for a single gene.

Many genes are associated with the diagnosis of autism. This is best illustrated by the long list of de novo single nucleotide variants (SNVs) now emerging in autism within the Simons Simplex Collection of families (Neale et al. Reference Neale, Kou, Liu, Ma'ayan, Samocha, Sabo, Lin, Stevens, Wang, Makarov, Polak, Yoon, Maguire, Crawford, Campbell, Geller, Valladares, Schafer, Liu, Zhao, Cai, Lihm, Dannenfelser, Jabado, Peralta, Nagaswamy, Muzny, Reid, Newsham, Wu, Lewis, Han, Voight, Lim, Rossin, Kirby, Flannick, Fromer, Shakir, Fennell, Garimella, Banks, Poplin, Gabriel, Depristo, Wimbish, Boone, Levy, Betancur, Sunyaev, Boerwinkle, Buxbaum, Cook, Devlin, Gibbs, Roeder, Schellenberg, Sutcliffe and Daly2012; O'Roak et al. Reference O'Roak, Deriziotis, Lee, Vives, Schwartz, Girirajan, Karakoc, Mackenzie, Ng, Baker, Rieder, Nickerson, Bernier, Fisher, Shendure and Eichler2012a; Reference O'Roak, Vives, Girirajan, Karakoc, Krumm, Coe, Levy, Ko, Lee, Smith, Turner, Stanaway, Vernot, Malig, Baker, Reilly, Akey, Borenstein, Rieder, Nickerson, Bernier, Shendure and Eichler2012b; Sanders et al. Reference Sanders, Murtha, Gupta, Murdoch, Raubeson, Willsey, Ercan-Sencicek, Dilullo, Parikshak, Stein, Walker, Ober, Teran, Song, El-Fishawy, Murtha, Choi, Overton, Bjornson, Carriero, Meyer, Bilguvar, Mane, Sestan, Lifton, Gunel, Roeder, Geschwind, Devlin and State2012). These SNVs may be found to have broad pleiotropic manifestations beyond ASD per se. An example of classical pleiotropy for psychiatric diagnosis can be found for the gene diacylglycerol kinase eta (DGKH). It has been implicated in not only bipolar disorder, but also unipolar depression and attention-deficit/hyperactivity disorder (ADHD; Weber et al. Reference Weber, Kittel-Schneider, Gessner, Domschke, Neuner, Jacob, Buttenschon, Boreatti-Hummer, Volkert, Herterich, Baune, Gross-Lesch, Kopf, Kreiker, Nguyen, Weissflog, Arolt, Mors, Deckert, Lesch and Reif2011). Also, the gene synaptosomal-associated protein 25 (SNAP25) has been associated with ADHD and antisocial disorders, and it may be associated with lower reward dependence and higher novelty seeking (Basoglu et al. Reference Basoglu, Oner, Ates, Algul, Bez, Cetin, Herken, Erdal and Munir2011).

Epigenesis

Dysregulation of DNA methylation and histone modification are likely to play a major role in the pathophysiology of ASD and other neuropsychiatric illness (Shulha et al. Reference Shulha, Cheung, Whittle, Wang, Virgil, Lin, Guo, Lessard, Akbarian and Weng2012). Studies of post-mortem prefrontal brain tissue have revealed epigenetic profile alteration for literally hundreds of loci, notably, ones implicated in neurodevelopment. These epigenetic effects may converge on common developmental pathways in autism.

Convergent neurodevelopmental pathogenesis

There is also strong evidence from post-mortem brain studies that multiple genes may disrupt common neurodevelopmental pathways in autism. Voineagu et al. (Reference Voineagu, Wang, Johnston, Lowe, Tian, Horvath, Mill, Cantor, Blencowe and Geschwind2011) found that gene expression influencing cortical patterning is markedly altered in ASD. Their findings, taken as a whole, indicate that heterogeneous gene splicing and transcriptional dysregulation may underlie neurodevelopmental pathogenesis in autism.

Summary

The enterprise of gene discovery for neuropsychiatric disorders is revealing how multiple etiologies can contribute to one phenotype and multiple phenotypes can be manifested for one etiology. Once causal factors for brain-based disorders are identified, a new challenge emerges: determining how multiple pathogenetic factors conspire to disrupt common underlying neurodevelopmental mechanisms.