Copy Number Variants in Extended Autism Spectrum Disorder Families Reveal Candidates Potentially Involved in Autism Risk

Copy number variations (CNVs) are a major cause of genetic disruption in the human genome with far more nucleotides being altered by duplications and deletions than by single nucleotide polymorphisms (SNPs). In the multifaceted etiology of autism spectrum disorders (ASDs), CNVs appear to contribute significantly to our understanding of the pathogenesis of this complex disease. A unique resource of 42 extended ASD families was genotyped for over 1 million SNPs to detect CNVs that may contribute to ASD susceptibility. Each family has at least one avuncular or cousin pair with ASD. Families were then evaluated for co-segregation of CNVs in ASD patients. We identified a total of five deletions and seven duplications in eleven families that co-segregated with ASD. Two of the CNVs overlap with regions on 7p21.3 and 15q24.1 that have been previously reported in ASD individuals and two additional CNVs on 3p26.3 and 12q24.32 occur near regions associated with schizophrenia. These findings provide further evidence for the involvement of ICA1 and NXPH1 on 7p21.3 in ASD susceptibility and highlight novel ASD candidates, including CHL1, FGFBP3 and POUF41. These studies highlight the power of using extended families for gene discovery in traits with a complex etiology

Candidate gene association testing in the dissection of genetic causes for depressive disorders and the response to antidepressant treatment.

The main goal of this thesis is the identification of the susceptibility genes for MD and response to antidepressant treatment in order to gain a better understanding of its genetic causes. For this aim I performed the association testing of candidate genes in patients of the psychiatric clinic of Max-Planck-Institute for Psychiatry. Many factors affect the outcome of an genetic association study. For this reason I address the particularities and problems relevant for the power and effciency of association testing between the polymorphisms in candidate genes and clinical phenotypes in the first chapter of my thesis. Because of the large number of tests in current studies it is necessary to address the multiple testing problem. In last two chapters I test the association of candidate genes with MDD and response to antidepressant treatment