Person:

Levy, Deborah

A number of mixture modeling approaches assume both normality and independent observations. However, these two assumptions are at odds with the reality of many data sets, which are often characterized by an abundance of zero-valued or highly skewed observations as well as observations from biologically related (i.e., non-independent) subjects. We present here a finite mixture model with a zero-inflated Poisson regression component that may be applied to both types of data. This flexible approach allows the use of covariates to model both the Poisson mean and rate of zero inflation and can incorporate random effects to accommodate non-independent observations. We demonstrate the utility of this approach by applying these models to a candidate endophenotype for schizophrenia, but the same methods are applicable to other types of data characterized by zero inflation and non-independence.

Summary In the process of generating presumably clonal human induced pluripotent stem cells (hiPSCs) from two carriers of a complex structural rearrangement, each having a psychotic disorder, we also serendipitously generated isogenic non-carrier control hiPSCs, finding that the rearrangement occurs as an extrachromosomal marker (mar) element. All confirmed carrier hiPSCs and differentiated neural progenitor cell lines were found to be mosaic. We caution that mar elements may be difficult to functionally evaluate in hiPSC cultures using currently available methods, as it is difficult to distinguish cells with and without mar elements in live mosaic cultures.

Clozapine is a particularly effective antipsychotic medication but its use is curtailed by the risk of clozapine-induced agranulocytosis/granulocytopenia (CIAG), a severe adverse drug reaction occurring in up to 1% of treated individuals. Identifying genetic risk factors for CIAG could enable safer and more widespread use of clozapine. Here we perform the largest and most comprehensive genetic study of CIAG to date by interrogating 163 cases using genome-wide genotyping and whole-exome sequencing. We find that two loci in the major histocompatibility complex are independently associated with CIAG: a single amino acid in HLA-DQB1 (126Q) (P=4.7×10−14, odds ratio, OR=0.19, 95% CI 0.12–0.29) and an amino acid change in the extracellular binding pocket of HLA-B (158T) (P=6.4×10−10, OR=3.3, 95% CI 2.3–4.9). These associations dovetail with the roles of these genes in immunogenetic phenotypes and adverse drug responses for other medications, and provide insight into the pathophysiology of CIAG.