Erika L. Nurmi, Ph.D. - US grants

DESCRIPTION (provided by applicant): The proposed five-year K23 Mentored Patient-Oriented Research Career Development Award outlines a program of career development and research activities that will assist the principal investigator to transition to an independent research career and prepare her to tackle the challenges ahead in unraveling the genetic basis of complex psychiatric phenotypes. The innovative research plan details an approach to mapping risk for a strongly genetic subtype of obsessive compulsive (OCD) and comorbid tic disorders by generating and analyzing whole-exome sequence in select families to identify risk alleles. These efforts will be guided by pilot identity-by-descent, homozygosity, and copy number variant data in the comprehensively phenotyped OCD Collaborative Genetic Study (OCGS) multiplex family dataset. The OCD+tic phenotype is an ideal complex disorder for next generation genetic mapping. The clear phenotype, possibly reduced heterogeneity, and strong genetic effects make it an excellent candidate for the application of methodologies recently proven successful in Mendelian disorders. While the principle investigator has a strong background in child psychiatry and molecular genetics, the knowledge and skills required to master emerging genetic technologies such as next generation sequencing (NGS) are novel and complex. The short-term goals of this application are to gain proficiency in the methods that will drive the field over the coming decades, learn the statistical, computational, and informatics tools that will support this research, continue to develop skills in study design and interpretation, and refine and incorporate clinical and phenotyping skills. A program of coursework, supervision, and hands-on application of these approaches will equip the applicant in the long-term to integrate molecular, computational, and phenotypic data to make meaningful contributions to the field of psychiatric genetics. This award will help the candidate to establish an independent research career, position herself on the front of these new advances, and bring the lessons learned to the field of child psychiatry. PUBLIC HEALTH RELEVANCE: The proposed five-year K23 Mentored Patient-Oriented Research Career Development Award outlines a program of career development and research activities that will assist the principal investigator to transition to an independent research career and prepare her to tackle the challenges ahead in unraveling the genetic basis of complex psychiatric traits. The innovative research plan details an approach to finding risk genes for a strongly genetic subtype of obsessive compulsive (OCD) and comorbid tic disorders by analyzing the full protein-coding sequence of the genome in select families of the comprehensively characterized OCD Collaborative Genetic Study (OCGS). A program of coursework, supervision, and hands-on application of these approaches will equip the applicant in the long-term to integrate molecular, computational, and clinical data to make meaningful contributions to the field of psychiatric genetics.

ABSTRACT The limited utility of employing categorical diagnoses in genetic studies of complex psychiatric disorders has led the field to explore dimensional measures of functional neurocognitive phenotypes as more proximal to brain biology. A promising candidate for the study of impulsivity-related mental illness is the construct of inhibitory cognitive control (ICC). Research has shown that impaired ICC, manifest behaviorally as impulsivity, is a core feature of disorders such as attention-deficit/hyperactivity (ADHD) and bipolar (BPD) disorders. Our primary aim is to examine whether alleles associated with ICC in healthy individuals can explain a portion of the genetic risk for ADHD and BPD. We will explore ICC in an extensively phenotyped healthy control population of 1600 individuals. Quantitative measures of impulsive choice and impulsive action, respectively using the delayed discounting task (DDT) and stop signal task (SST), have been assessed in this sample, and will be combined to create a measure of ICC. A genome-wide polygenic risk score for ICC will be validated in two independent samples. Correlation between ICC polygenic risk in the LA2K dataset and publicly available psychiatric populations will test for shared genetic risk. We hypothesize that those disorders where impulse control is a core feature, such as ADHD and BPD, will show greater genetic overlap with ICC phenotypes than other disorders. Furthermore, we seek to establish genetic ties to functional gene networks by testing ICC- associated variants for enrichment in ICC-related genetic pathways. This project will support ICC as a key, inherited trait conferring vulnerability to impulsivity-related mental illness and may ultimately suggest new avenues for behavioral and pharmacological interventions that target ICC.

Abstract Weight gain and metabolic dysfunction are common, serious side effects of many psychiatric medications, especially antipsychotic drugs. These effects are amplified in children and can severely compromise physical health and interfere with psychiatric treatment. While the mechanism of antipsychotic-induced weight gain (AIWG) is poorly understood, studies in rodents have argued for a central role of gut microbes. Our team showed a similar effect in children taking the antipsychotic risperidone (RSP). We further hypothesized that gut microbes could impact weight and metabolism by altering bile acid (BA) signaling. Primary BAs made in the liver are converted to secondary BAs by gut bacteria. These two types of BAs have opposing effects on the liver farnesoid X receptor (FXR), involved in metabolism and energy balance. In support of this model, we determined that RSP exposure in youth with autism resulted in plasma BA elevations. The BA balance was distinct between those who gained weight on RSP and those who did not. Higher primary BAs favored weight gain, while higher secondary BAs were protective. This pattern was repeated in a small independent sample of children taking RSP and interestingly, in children taking selective serotonin reuptake inhibitors (SSRIs). Therefore, this proposal seeks to test this novel gut microbe-BA model of AIWG in children started on RSP by their physician for any mental illness. We will follow 60 children during the first 8 weeks of RSP treatment and collect blood and stool to measure BAs and gut microbes respectively. In those who gain weight with RSP treatment compared to those who do not, we predict a decrease in the abundance of gut bacteria capable of converting primary to secondary BAs and a resultant shift in the BA pool toward primary BAs. If proven, this model could guide clinical interventions to prevent metabolic side effects, as several potential treatments impacting this system are currently available for other uses. Additionally, this mechanism may apply more globally to other drug classes and possibly to obesity and metabolic dysfunction in general.