Whole Genome Linkage Analysis in a Large Multigenerational Family From Brazil and Case Control Exploration of Linkage Regions

Substantial evidence from family and twin studies confirms the importance of genes in influencing susceptibility to Bipolar Disorder (BPD) and Depression. Genome- wide association studies have uncovered a few genetic variants of small effect that explain only a fraction of the total heritability of these disorders, and linkage studies have not been able to identify consistent and replicable findings, possibly due to phenotypic complexity and genetic heterogeneity. Large multigenerational families work as powerful samples to mapping loci for complex diseases as they segregate fewer disease causing genes than a collection of independent nuclear families. These fewer genes segregating may also be more highly penetrant and easier to detect in linkage studies.This study performed a whole genome linkage scan of a large multigenerational family from Brazil segregating a severe form of BPD and unipolar depression with the aim of localising and identifying genetic variants that contribute to the development of BPD. The ‘Brazilian Bipolar Family’ (BBF) is one of the largest reported in the literature. Three hundred and eight family members were interviewed using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID) and the Kiddie-SADS-Present and Lifetime Version (K-SADS-PL) and three- hundred and twenty-four family members were genotyped using the Affymetrix 10K array. Parametric and non-parametric linkage analyses were performed using four hierarchical phenotype models. Four genome-wide significant linkage regions were identified on chromosomes 2p23.1-p22.3, 3p24.3-p24.1, 11p15.4, and 12q24.22- q24.32, and four suggestive linkage regions were identified on chromosomes 1p22.2- p21.3, 1q21.1-q21.3, 12p13.32-p13.31, and 22q11.21-q12.1, which either conferred specific risk to BPD, unipolar depression, or provided evidence for a general mood disorder liability.To determine the role of the identified linkage regions in sporadic bipolar and depression cases, I performed a case control association analysis using bipolar and depression case control cohorts. None of the linkage regions identified in the BBF were found to be associated with BPD or depression. The future aim of this project is to determine the functional variants within the identified linkage regions that may be contributing to the development of mood disorders in the BBF <br/>through sequencing analysis, which is already underway.<br/>

Name dc:type.qualificationname

Doctor of Philosophy

Level dc:type.qualificationlevel

Doctoral Thesis

Grantor dc:publisher.institution

King's College London

Year dc:date.issued

2012

Author dc:creator

• Alsabban, Shaza

Advisors dc:contributor.advisor

• McGuffin, Peter
• Breen, Gerome Daniel

Language dc:language

eng

Identifier

oai:kclpure.kcl.ac.uk:studenttheses/c54791d5-6782-4b32-b121-def3b3acdb41

OAI identifier oai:identifier

oai:kclpure.kcl.ac.uk:studenttheses/c54791d5-6782-4b32-b121-def3b3acdb41