Open Access

Afsheen Yousaf

• Neuropsychiatric disorders are complex, highly heritable but incompletely understood disorders. The clinical and genetic heterogeneity of these disorders poses a significant challenge to the identification of disorder related biomarkers. Besides significant progress in unveiling the genetic basis of these disorders, the underlying causes and biological mechanisms remain obscure. With the advancement in the array, sequencing, and big data technologies, a huge amount of data is generated from individuals across different platforms and in various data structures. But there is a paucity of bioinformatics tools that can integrate this plethora of data. Therefore, there is a need to develop an integrative bioinformatics data analysis tool that combines biological and clinical data from different data types to better understand the underlying genetics. This thesis presents a bioinformatics pipeline implementing data from different platforms to provide a thorough understanding of the genetic etiology of a neuropsychiatric quantitative as well as a qualitative trait of interest. Throughout the thesis, we present two aspects: one is the development and architecture of the bioinformatics pipeline named MApping the Genetics of neuropsychiatric traits to the molecular NETworks of the human brain (MAGNET). The other part demonstrates the implementation and usefulness of MAGNET analysing large Autism Spectrum Disorder (ASD) cohorts. MAGNET is a freely available command-line tool available on GitHub (https://github.com/SheenYo/MAGNET). It is implemented within one framework using data integration approaches based on state-of-the-art algorithms and software to ultimately identify the genes and pathways genetically associated with a trait of interest. MAGNET provides an edge over the existing tools since it performs a comprehensive analysis taking care of the data handling and parsing steps necessary to communicate between the different APIs (Application Program Interface). Thus, this avoids the in-between data handling steps required by researchers to provide output from one analysis to the next. Moreover, depending on the size of the dataset users can deduce important information regarding their trait of interest within a time frame of a few days. Besides gaining insights into genetic associations, one of the central features is the mapping of the associated genes onto developing human brain implementing transcriptome data of 16 different brain regions starting from the 5th post-conceptional week to over 40 years of age. In the second part as proof of concept, we implemented MAGNET on two ASD cohorts. ASD is a group of psychiatric disorders. Clinically, ASD is characterized by the following psychopathology: A) limitations in social interaction and communication, and B) restricted, repetitive behavior. The etiology of this disorder is extremely complex due to its heterogeneous clinical traits and genetics. Therefore, to date, no reliable biomarkers are identified. Here, the aim is to characterize the genetic architecture of ASD taking into account the two aforementioned ASD diagnostic domains. As well as to investigate if these domains are genetically linked or independent of each other. Moreover, we addressed the question if these traits share genetic risk with the categorical diagnosis of ASD and how much of the phenotypic variance of these traits can be explained by the underlying genetics. We included affected individuals from two ASD cohorts, i.e. the Autism Genome Project (AGP) and a German cohort consisting of 2,735 and 705 families respectively. MAGNET was applied to each of the ASD subdomains as a quantitative dependent variable. MAGNET is divided into five main sections i.e. (1) quality check of the genotype data, (2) imputation of missing genotype data, (3) association analysis of genotype and trait data, (4) gene-based analysis, and (5) enrichment analysis using gene expression data from the human brain. MAGNET was applied to each of the individual traits in each cohort to perform quality control of the genetic data and imputed the missing data in an automated fashion. MAGNET identified 292 known and new ASD risk genes. These genes were subsequently assigned to biological signaling pathways and gene ontologies via MAGNET. The underlying biological mechanisms converged with respect to neuronal transmission and development processes. By reconciling these genes with the transcriptome of the developing human brain, MAGNET was able to identify that the significant genes associated with the subdomains are expressed at specific time points in brain areas such as the hippocampus, amygdala, and cortical regions. Further, we found that ASD subdomains related to domain A but not to domain B have a shared genetic etiology.