File Download
  Links for fulltext
     (May Require Subscription)
Supplementary

postgraduate thesis: Genome-wide association analyses on complex diseases: from single-nucleotide polymorphism to copy numbervariation

TitleGenome-wide association analyses on complex diseases: from single-nucleotide polymorphism to copy numbervariation
Authors
Issue Date2013
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Wong, H. E. [黃凱敏]. (2013). Genome-wide association analyses on complex diseases : from single-nucleotide polymorphism to copy number variation. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5053409
AbstractComplex diseases, unlike Mendialian diseases, are often characterized by genetic heterogeneity and multifactorial inheritance, involving defects in genes from the same or multiple alternative pathways. Many congenital diseases and psychiatric disorders are complex diseases, and incur heavy health care burden on the society. With the advancement in high-throughput genotyping technologies and the availability of the human single nucleotide polymorphism (SNP) catalogue, genome-wide association study (GWAS) has been widely used to investigate the genetic component of complex diseases. Copy number variations (CNV) can also be identified using the data from the same SNP array. Aiming to identify more disease susceptibility loci for complex diseases, separate GWAS using a case-control design were conducted on anorectal malformations (ARMs) and schizophrenia. ARMs are rare congenital diseases with heterogeneous phenotypes which could probably be explained by the genetic heterogeneity among patients, while schizophrenia is a common psychiatric disorder that is well known for its multigenic inheritance. The GWAS studies on ARM and schizophrenia included 4,369 (patients: N=363; controls: N=4,006) and 1,231 Han Chinese (patients: N=381; controls: N=850) respectively. The two studies were mainly focused on investigating the contribution of rare CNVs to the diseases, involving analyses on global CNV burden, rare CNV association, protein-protein interaction (PPI) network, pathway and chromosomal aberrations. The associations of SNPs with ARMs were also examined. Apart from elucidating the genetic components in these two diseases, a systematic analysis on four CNV detection programs (CNV partition, PennCNV, QuantiSNP and iPattern) was also undertaken. In the study of schizophrenia, a new approach in CNV filtering which was based on latent class analysis was adopted to gather information from multiple CNV prediction programs. The study of ARMs revealed 79 genes which were disrupted by CNVs in patients only. In particular, a de novo duplication of DKK4 (an antagonist of WNT signaling) was identified, and addition of Dkk4 protein was demonstrated to cause ARMs in mice. Another 10 genes uniquely disrupted in ARMs patients are also related to WNT signaling. Interestingly, this pathway was also significantly inferred by CNV in patients with schizophrenia. A different set of genes related to WNT signaling was disrupted in ARMs patients and patients with schizophrenia. WNT signaling is crucial for the development of multiple parts in the embryo. The contribution of different WNT signaling pathways at different development stages may vary. Apart from the WNT signaling pathway, other genes with biological relevance were also implicated in the two studies through gene-network and pathway analyses. The results from these two GWAS studies support our existing understanding of complex diseases that defects in various interacting genes could contribute to the same disease. In summary, the CNV results from the two studies have demonstrated the genetic heterogeneity nature of these two complex diseases. The findings also uncovered a set of putative disease candidate genes, which can be used as reference materials for future genetic research for ARMs and schizophrenia.
DegreeDoctor of Philosophy
SubjectAbnormalities, Human - Genetic aspects.
Schizophrenia - Genetic aspects.
Dept/ProgramPsychiatry
Persistent Identifierhttp://hdl.handle.net/10722/188290

 

DC FieldValueLanguage
dc.contributor.authorWong, Hoi-man, Emily.-
dc.contributor.author黃凱敏.-
dc.date.accessioned2013-08-27T08:03:19Z-
dc.date.available2013-08-27T08:03:19Z-
dc.date.issued2013-
dc.identifier.citationWong, H. E. [黃凱敏]. (2013). Genome-wide association analyses on complex diseases : from single-nucleotide polymorphism to copy number variation. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5053409-
dc.identifier.urihttp://hdl.handle.net/10722/188290-
dc.description.abstractComplex diseases, unlike Mendialian diseases, are often characterized by genetic heterogeneity and multifactorial inheritance, involving defects in genes from the same or multiple alternative pathways. Many congenital diseases and psychiatric disorders are complex diseases, and incur heavy health care burden on the society. With the advancement in high-throughput genotyping technologies and the availability of the human single nucleotide polymorphism (SNP) catalogue, genome-wide association study (GWAS) has been widely used to investigate the genetic component of complex diseases. Copy number variations (CNV) can also be identified using the data from the same SNP array. Aiming to identify more disease susceptibility loci for complex diseases, separate GWAS using a case-control design were conducted on anorectal malformations (ARMs) and schizophrenia. ARMs are rare congenital diseases with heterogeneous phenotypes which could probably be explained by the genetic heterogeneity among patients, while schizophrenia is a common psychiatric disorder that is well known for its multigenic inheritance. The GWAS studies on ARM and schizophrenia included 4,369 (patients: N=363; controls: N=4,006) and 1,231 Han Chinese (patients: N=381; controls: N=850) respectively. The two studies were mainly focused on investigating the contribution of rare CNVs to the diseases, involving analyses on global CNV burden, rare CNV association, protein-protein interaction (PPI) network, pathway and chromosomal aberrations. The associations of SNPs with ARMs were also examined. Apart from elucidating the genetic components in these two diseases, a systematic analysis on four CNV detection programs (CNV partition, PennCNV, QuantiSNP and iPattern) was also undertaken. In the study of schizophrenia, a new approach in CNV filtering which was based on latent class analysis was adopted to gather information from multiple CNV prediction programs. The study of ARMs revealed 79 genes which were disrupted by CNVs in patients only. In particular, a de novo duplication of DKK4 (an antagonist of WNT signaling) was identified, and addition of Dkk4 protein was demonstrated to cause ARMs in mice. Another 10 genes uniquely disrupted in ARMs patients are also related to WNT signaling. Interestingly, this pathway was also significantly inferred by CNV in patients with schizophrenia. A different set of genes related to WNT signaling was disrupted in ARMs patients and patients with schizophrenia. WNT signaling is crucial for the development of multiple parts in the embryo. The contribution of different WNT signaling pathways at different development stages may vary. Apart from the WNT signaling pathway, other genes with biological relevance were also implicated in the two studies through gene-network and pathway analyses. The results from these two GWAS studies support our existing understanding of complex diseases that defects in various interacting genes could contribute to the same disease. In summary, the CNV results from the two studies have demonstrated the genetic heterogeneity nature of these two complex diseases. The findings also uncovered a set of putative disease candidate genes, which can be used as reference materials for future genetic research for ARMs and schizophrenia.-
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.source.urihttp://hub.hku.hk/bib/B50534099-
dc.subject.lcshAbnormalities, Human - Genetic aspects.-
dc.subject.lcshSchizophrenia - Genetic aspects.-
dc.titleGenome-wide association analyses on complex diseases: from single-nucleotide polymorphism to copy numbervariation-
dc.typePG_Thesis-
dc.identifier.hkulb5053409-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplinePsychiatry-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.5353/th_b5053409-
dc.date.hkucongregation2013-

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats