dnAGEnetics: genomic copy number variants and parental age as risk factors for psychiatric disorders

Abstract

Introduction: Schizophrenia is a debilitating psychiatric disorder with a life-time risk of 0.46 – 1% in the general population. It is characterized by psychotic symptoms, including delusions and hallucinations. Its predisposition is influenced by a complex interaction of genetic and environmental factors. Early genetic studies in schizophrenia were based on linkage studies and association testing, more recently complemented by genome-wide association studies. These genomic microarray studies also allow for the systematic genome-wide analysis of submicroscopic cytogenetic variation, i.e. genomic copy number variation (CNV) that includes deletions and duplications of more than 1 kb in size. CNVs are associated with different diseases. In this thesis we aimed to investigate the role of CNV burden as probable risk factor for schizophrenia. Another risk factor often mentioned for schizophrenia is increased age of parents. Epidemiological studies suggested an association between increased parental age and schizophrenia, autism, and bipolar disorder, although different associations have been found. These different associations raised the question whether there are diverse parental age risk effects for psychiatric diagnoses. Furthermore, we questioned whether an increased CNV mutational burden in the offspring could (partly) explain the association between psychiatric disorders and increased parental age. Methods: In the first studies we performed genome-wide CNV analyses in schizophrenia patients and healthy control subjects. We investigated rare gene-rich variants, and all reliably detected CNVs at ≥50 kb, respectively. In the last two studies we investigated the role of parental age on adverse outcomes in the offspring. First, we investigated whether parental age has different risk effects for four major psychiatric disorders. Second, we tested the hypothesis of a direct correlation between parental age and CNV burden in the offspring. Results: In the first studies we show that the overall CNV rate, and especially deletions, is increased in individuals with schizophrenia. Our results show that rare CNVs play a role in schizophrenia susceptibility and we identify three neuronal genes as candidate genes for this disorder. Furthermore, three large recurrent deletions are significantly associated with schizophrenia. In the third study we show that increased age of the father is a risk factor for neuropsychiatric disorders. We find different associations for autism and schizophrenia on the one hand and affective disorders on the other hand. We suggest selection into late fatherhood as the most promising hypothesis behind these associations. In the last study we provide strong evidence that increased parental age is not involved in global CNV burden in the offspring. Conclusions: Our findings indicate that both CNV load and increased parental age are risk factors for neuropsychiatric disorders, in particular schizophrenia. Remarkably, our findings suggest that both factors are independent events in the risk for neuropsychiatric disorders, implying that parental age does not augment disease vulnerability via increased CNV burden in the offspring.