Fifth, one historical candidate gene (DISC1) studied a rare genetic event, the t(1;11) (q42.1;q14.3) translocation in a Scottish pedigree where the propositus did not have schizophrenia. The genetic linkage results in this pedigree point to a broad phenotype (LOD 7.1 for recurrent major depression, bipolar disorder, or schizophrenia). The status of DISC1 is controversial despite its entry into the literature nearly 15 years ago 45 (see also a rebuttal 46). The most critical issue is that no other genetic study has independently implicated DISC1 (i.e., met contemporary significance thresholds for rare exonic variation, rare CNVs, or common variation). 11, 18, 19, 47, 48 In contrast, many other rare variant associations have genetic replication evidence. For example, early-onset Alzheimer’s disease is caused by rare mutations in APP, PSEN1, and PSEN2.49 Unlike the singular DISC1 event, these associations are highly compelling as they replicate in many different pedigrees (90 families for APP, 405 for PSEN1, and 22 for PSEN2, see URLs). Similarly, the CNV associations for autism and schizophrenia replicate in large samples worldwide. 17
