The Psychiatric Cell Map Initiative: A Convergent Systems Biological Approach to Illuminating Key Molecular Pathways in Neuropsychiatric Disorders

Abstract

Although gene discovery in neuropsychiatric disorders, including autism spectrum disorder, intellectual disability, epilepsy, schizophrenia, and Tourette disorder, has accelerated, resulting in a large number of molecular clues, it has proven difficult to generate specific hypotheses without the corresponding datasets at the protein complex and functional pathway level. Here, we describe one path forward-an initiative aimed at mapping the physical and genetic interaction networks of these conditions and then using these maps to connect the genomic data to neurobiology and, ultimately, the clinic. These efforts will include a team of geneticists, structural biologists, neurobiologists, systems biologists, and clinicians, leveraging a wide array of experimental approaches and creating a collaborative infrastructure necessary for long-term investigation. This initiative will ultimately intersect with parallel studies that focus on other diseases, as there is a significant overlap with genes implicated in cancer, infectious disease, and congenital heart defects.

Multi-hit autism genomic architecture evidenced from consanguineous families with involvement of FEZF2 and mutations in high-risk genes

“…For the FEZF2 allele-unlinked families, the DAPPLE network is also significant for both direct and indirect nodes (Direct Edges Count P = 3.49 x 10 -2 ; Seed Indirect Degrees Mean P = 1.99 x 10 -2 ; CI Degrees Mean P=1.99 x 10 -3 ). Interestingly, mutations found in de novo CNVs of FEZF2 allele-unlinked families underline the importance of synaptic networks as already reported (5,6,(33)(34)(35). In contrast, results from transmitted and de novo CNVs of FEZF2 allelelinked and unlinked families point to distinct gene classes with adhesion proteins involved in hemophilic interactions, such as clustered protocadherins (36,37), that are known to be involved in the establishment of the diversity of neural circuit assemblies and olfaction pathways.…”

“…The linkage analysis revealed several genetic loci overlapping between pedigrees with strong support for linkage with logarithm of odds (LOD) scores ranging from 3.6 to 5.8 ( Supplementary Table S2). One region of 133 kb that includes the FEZF2 gene at 3p14.2 was identified in five families (2,5,6,18,23) and had a higher LOD score of 5.8 (Figure 1A-B). The FEZF2 gene encodes the transcription factor required for the specification of corticospinal motor neurons (10,11,12).…”

“…ASD is a phenotypically and genetically heterogeneous neurodevelopmental condition that is characterized by deficits in reciprocal social interaction, repetitive behavior patterns, and restricted interests (3), with a prevalence as high as 1 in 68 children (4). Both de novo and transmitted multiple definitive risk-carrying copy number variations (CNVs), protein-altering mutations, and/or non-coding alleles have been identified in ASD (5,6). Recent studies leveraged the statistical power afforded by rare de novo putatively damaging variants and have identified more than 65 strongly associated or highconfidence genes (5).…”

“…The most deleterious variants that are likely gene-disrupting in the highest confidence subset (False Discovery Rate, FDR ≤ 0.01) of these genes (n = 30) as a group confer ∼20-fold increase in risk (5). To date, there is very little evidence for a multi-hit hypothesis vis-á-vis these highly damaging de novo coding mutations (6). Willsey et al proposed a model with a single highly protein-disrupting mutation causing functional haploinsufficiency and thus sufficient to confer these very large risks (6).…”

“…To date, there is very little evidence for a multi-hit hypothesis vis-á-vis these highly damaging de novo coding mutations (6). Willsey et al proposed a model with a single highly protein-disrupting mutation causing functional haploinsufficiency and thus sufficient to confer these very large risks (6).…”