By Chelsea A. Jack and Mark B. Herzog
Two studies published this month—one about schizophrenia and the other about autism spectrum disorder—describe genetic and clinical heterogeneity among people with the disorders, suggesting that the diagnoses refer to many entities, not just one.
In the current issue of the American Journal of Psychiatry, Javier Arnedo et al. postulate that the heritability of schizophrenia (SZ) is not “missing,” as has been previously suggested. Instead, Arnedo et al. argue that there are many forms of SZ, each caused by multiple, interacting genotypic networks and each with different clinical presentations. In three independent genome-wide association studies (GWAS), the authors first identified 42 interactive single-nucleotide polymorphism sets (SNP sets) associated with 70 percent or greater risk of schizophrenia. These findings were replicated in two additional independent samples where 31 and 30 of those initial 42 SNP sets were re-identified. Their test for replicability yielded 81 percent of the SNP sets at risk. Following SNP identification, 17 genotypic networks, varying in size and complexity, were found to be disjointed, sharing neither SNPs nor subjects—again, what had gone under the single label SZ turned out to be genetically heterogeneous.
In this month’s issue of Nature Medicine, Ryan Yuen et al. report an equally heterogeneous understanding of autism spectrum disorder (ASD). Using whole-genome sequencing (WGS) on 85 ASD-affected quartet families (i.e., families with 2 parents and 2 ASD-affected siblings), the authors found that 69.4 percent of the affected siblings carried different ASD-relevant mutations. In terms of clinical outcomes, “siblings with discordant mutations tended to demonstrate more clinical variability than those who shared a risk variant.” In contrast to previous autism research on simplex families (i.e., families with one affected child), WGS on quartet families in this study found heterogeneity not only among hundreds of susceptibility loci, but also between siblings. As Arnedo et al. concluded in the SZ case, Yuen et al. also found substantial genetic heterogeneity in ASD.
Both studies have significant implications for the development of personalized treatments for SZ and ASD. As Arnedo et al. write, “our results hold promise for the emergence of a new era in clinical psychiatry in which person-centered treatment of complex disorders can be guided by reliable assessments of well-validated clinical syndromes and their specific causes.”
The Arnedo et al. publication was met, however, with a detailed and biting online comment by Gerome Breen et al., which questioned the report’s major conclusions. For example, Breen et al. raise sex, ethnicity, and linkage disequilibrium as confounds that yield spurious associations between SNPs and disease. Though Arnedo et al. responded to Breen et al. on the same online forum, the debate appears far from over.
These explorations of the genetic architecture of SZ and ASD are strikingly reminiscent of the exploration of the neural architecture of depression, which have been undertaken with neuroimaging technologies. Just last year Helen Mayberg, the neurologist who pioneered deep brain stimulation as a treatment for depression, published an essay describing her search for a neural signature of depression. Contrary to her hypothesis and hope, she could not find one. Depression isn’t a monolith, neurologically or clinically. Just as the neurological heterogeneity of depression came as somewhat of a surprise to Mayberg, the genetic heterogeneity of SZ has apparently surprised many readers of the paper by Arnedo et al.
Though Mayberg did not discover the neural signature she was looking for, she remains cautiously optimistic that beginning to understand the subtypes of depression will ultimately yield relief for patients and their families, specifically by assisting with assessing and tailoring treatments. There seems every reason to be hopeful that results such as those reported by Arnedo et al. and Yuen et al. will also ultimately help bring relief to people with SZ and ASD. As researchers seek to replicate the sorts of findings described here, it will be important to help patients and families understand how much time may elapse between the report of such intriguing findings and the delivery of the treatments they so desperately need.