Table 1 Unanswered questions about DISC1

The pedigree

Have the karyotypes from the late 1960s been updated with modern methods? Were the key Blackwood et al.²⁰ linkage analyses based on the Jacobs et al.¹⁹ karyotypes?

Three structural variants were reported to segregate in this pedigree: which can be verified with modern methods? Which segregate with psychiatric phenotypes? What was the justification for focusing solely on t(1;11) (q42.1;q14.3)? Why was the rest of the pedigree not reported?

The most recent phenotype reports are from 2001. How have the diagnoses changed? What effect do changes in diagnosis have on the linkage results? Given that linkage results can be sensitive to influential subjects, what do sensitivity analyses show?

The phenotypes that appear to track with t(1;11) (q42.1;q14.3) are dissimilar to other rare structural variants where schizophrenia, autism, epilepsy and/or mental retardation are associated. The prominence of recurrent MDD is worrying. Why is this pedigree different? Does the absence of these other conditions suggest that DISC1 is not a true schizophrenia risk factor?

The focus on DISC1

It is possible that the chr1 DISC1 side of the breakpoint is not centrally important: what role does the chr11 side of the breakpoint play (for example, the predicted lincRNA)?

Much rests on the assumption that the translocation that impacts DISC1 is causal. However, efforts to falsify this genomic hypothesis are few. How can genomic data be used to more clearly implicate or exclude DISC1?

Genetic results

The DISC1 translocation is private to a single pedigree. The largest and most rigorously conducted genomic studies of common variation, rare variation and copy number variation provide no support for a role of DISC1 in schizophrenia, bipolar disorder, autism and MDD. A rigorous analysis of pleomorphic effects similarly found no evidence for a role for DISC1. Do these negatives exclude DISC1 with confidence?