Multi-scale consequences of variants in the schizophrenia risk gene SETD1A in a population isolate.

Project Summary.
Rare variants with large effects provide excellent opportunities to characterize causal mechanisms for complex
disorders. Recently, large-scale exome sequencing of schizophrenia found that rare protein-truncating and
missense variants in SET Domain Containing 1A (SETD1A) are associated with approximately 4- to 20-fold
increased risk for schizophrenia, making this the top risk gene (P = 2.0e-12) among about ten genes with strong
support. SETD1A encodes a chromatin modifying enzyme responsible for tri-methylation of lysine 4 on the
histone 3 tail (H3K4me3), an important histone modification at active promoters. Characterizing the effects of
SETD1A variants has emerged as one of the most exciting prospects to understand causal mechanisms
underlying risk for schizophrenia. However, interrogating these effects has been hindered by two critical
obstacles: First, since SETD1A variants are very rare, it has been difficult to ascertain sufficient numbers of
carriers to fully characterize SETD1A’s clinical phenotype. Second, in part for the same reason, there have been
no studies of naturally occurring SETD1A variants in human neural cells. Here, we propose experiments to
overcome both of these obstacles, leveraging our discovery of seven deleterious, nonsynonymous SETD1A
variants enriched in a locally accessible founder population, the Old Order Amish. We will recruit a total of 128
Amish carriers of SETD1A variants and their blood relatives, ascertain deep cognitive and psychiatric symptom
phenotypes, and test hypotheses regarding allelic heterogeneity, allele frequency dependence, dose
dependence, and interactions with polygenic risk from common variants. Next, we will obtain induced pluripotent
stem cells from a subset of these individuals to identify cellular and neurodevelopmental phenotypes,
characterize allelic heterogeneity at a cellular level, and test the hypothesis that cellular phenotypes can be
rescued by restoring levels of H3K4me3. Finally, we will test the hypothesis that SETD1A variants alter the
chromatin potential of developing neurons, using cutting-edge single-cell multi-omic technologies and network
modeling techniques. Our exciting preliminary results demonstrate that Amish-enriched SETD1A variants are
associated with increased risk for psychosis, cognitive deficits, reduced cellular proliferation, increased
vulnerability to DNA damage, inefficient formation of neural rosettes, deficits in neurite outgrowth, and
transcriptional signatures of premature cell cycle exit and premature maturation in neural stem cells.

Grant Number: 5R01MH129343-04
NIH Institute/Center: NIH
Principal Investigator: Seth Ament