White matter lesions (WMLs) are commonly observed in MRI scans of older individuals, and are considered to be markers of small vessel disease. WMLs have been associated with cognitive deficits and dementia, and due to their demonstrated high heritability, they can be studied as an endophenotype for dementia. Therefore, defining the genetic variation that leads to WMLs may contribute to a better understanding, prevention, diagnosis and treatment of dementia. To study genetic susceptibility loci for WMLs, the two common approaches in genetics were applied: candidate gene and genome wide association studies (GWAS). In the candidate gene approach, associations of sortilin-related receptor (SORL1) gene variants were observed with hippocampal and whole brain volumes in the Sydney Older Persons Study (SOPS) cohort. In addition, sex specific associations were observed for angiotensin (AGT) and angiotensin I-converting enzyme (ACE) gene polymorphisms with WMLs in males, and for paraoxonase 2 (PON2) gene polymorphism in female participants of the Personality and Total Health (PATH) Study. The study of APOE ε2 or ε4 alleles did not show any association with hippocampal or whole brain volumes or with total WMLs in the SOPS, the PATH or the Sydney Memory and Ageing Study (MAS) cohorts. Brain-derived neurotrophic factor (BDNF) polymorphism was not associated with WMLs in the PATH cohort either. In a GWAS performed on MAS participants, several polymorphisms in suggestive association (p < 10-5) with WMLs were identified. SNPs were located within genes implicated in neuronal survival and differentiation (CREB5), which contained four intronic SNPs in linkage disequilibrium, homocysteine metabolism (CUBN), cellular growth (DHX33), and endothelial function (FLJ20184). Other SNPs showing suggestive association were located in intergenic regions, including three SNPs on chromosome 4. In addition, the association of WMLs with variants in different candidate genes investigated in this thesis was examined, using the genotyping data available from GWAS. None of these SNPs showed any association with WMLs in the MAS cohort. This thesis has identified several susceptibility loci for WMLs for which suggestive association has been shown. Identification of the genetic contributors to the heritability of WMLs will require additional studies using larger cohorts.