Abstract
Most psychiatric and neurological disorders are characterized by a complex genetic background where many common variants (single-nucleotide polymorphisms, SNPs) show an association to disease. Nowadays, we are able to obtain the genotypes of millions of SNPs through array-based genotyping and genotype imputation, and compare allele frequencies between large groups of cases and healthy controls in a statistical framework called a genome-wide association study (GWAS). With GWAS, genetic variation can be linked to – and ultimately provide insight into – the development of disease.
This thesis aims to further unravel the role of common genetic variation in complex psychiatric and neurological diseases and describes a variety of findings. First, using results from large GWAS in schizophrenia, further insight was provided into the role of common genetic variants in the synapse through comprehensive gene set and pathway enrichment analyses. Second, in a multivariate GWAS of quantitative phenotypes related to stress and trauma-induced psychopathology, a genetic locus was discovered that is possibly involved in the stress response. Additionally, this locus was functionally linked to genes involved in various stress-related conditions. This study furthermore shows the potential of using accurately measured quantitative phenotypes instead of a binary clinical diagnosis as a phenotype in GWAS. Third, it was found that using polygenic risk scores capturing the combined effect of SNPs associated with posttraumatic stress disorder and depression, we are currently unable to predict the risk for developing these disorders after exposure to deployment stress, also when assessing the interaction between genetic risk and exposure to traumatic events. Finally, the genetic overlap between diseases was explored and the clinical relevance of genetic cross-disorder studies was outlined. Cross-disorder genetic analysis showed that common genetic risk for amyotrophic lateral sclerosis (ALS) partly overlaps with common genetic risk for schizophrenia. This genetic correlation is relevant in light of an increased neuropsychiatric burden in families of ALS patients and the occurrence of cognitive impairment as a symptom in ALS. Furthermore, ALS patients can suffer from cramps and fasciculations, caused by hyperexcitability in motor neurons. Similarly, hyperexcitability of the nervous system plays a major role in epilepsy. We therefore assessed the genetic overlap between these two neurological conditions, but found that ALS and epilepsy do not share polygenic risk.
This thesis aims to further unravel the role of common genetic variation in complex psychiatric and neurological diseases and describes a variety of findings. First, using results from large GWAS in schizophrenia, further insight was provided into the role of common genetic variants in the synapse through comprehensive gene set and pathway enrichment analyses. Second, in a multivariate GWAS of quantitative phenotypes related to stress and trauma-induced psychopathology, a genetic locus was discovered that is possibly involved in the stress response. Additionally, this locus was functionally linked to genes involved in various stress-related conditions. This study furthermore shows the potential of using accurately measured quantitative phenotypes instead of a binary clinical diagnosis as a phenotype in GWAS. Third, it was found that using polygenic risk scores capturing the combined effect of SNPs associated with posttraumatic stress disorder and depression, we are currently unable to predict the risk for developing these disorders after exposure to deployment stress, also when assessing the interaction between genetic risk and exposure to traumatic events. Finally, the genetic overlap between diseases was explored and the clinical relevance of genetic cross-disorder studies was outlined. Cross-disorder genetic analysis showed that common genetic risk for amyotrophic lateral sclerosis (ALS) partly overlaps with common genetic risk for schizophrenia. This genetic correlation is relevant in light of an increased neuropsychiatric burden in families of ALS patients and the occurrence of cognitive impairment as a symptom in ALS. Furthermore, ALS patients can suffer from cramps and fasciculations, caused by hyperexcitability in motor neurons. Similarly, hyperexcitability of the nervous system plays a major role in epilepsy. We therefore assessed the genetic overlap between these two neurological conditions, but found that ALS and epilepsy do not share polygenic risk.
Original language | English |
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Awarding Institution |
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Award date | 12 Mar 2019 |
Place of Publication | [Utrecht] |
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Print ISBNs | 978-90-393-7097-1 |
Publication status | Published - 12 Mar 2019 |
Keywords
- GWAS
- SNP
- genetics
- genetic correlation
- pleiotropy
- cross-disorder
- psychiatry
- neurology