Population‐Based Genetic Studies: The Search for Causative Variants in Parkinson's Disease

In complex disorders such as Parkinson’s disease (PD), individual disease risk is determined by genetic, environmental, and demographic factors, as well as interactions between them. The estimated genetic component (heritability) of PD is 25% to 34%. For complex forms of PD, knowledge of heritability has been increased through approaches such as candidate gene studies and familial genetics, which have discovered common risk variants in the genes, LRRK2 and GBA. However, the most pivotal influence on progress in this field has been the introduction of a hypothesis-free genetic strategy: the genome-wide association study (GWAS). Additionally, subsequent introduction of a statistical approach to the GWAS strategy (i.e., the meta-analysis of multiple independent GWASs) has helped to increase power and reduce false-positive findings. To date, these strategies have identified more than 20 susceptibility loci for PD, including MAPT, SNCA, HLA-DRB5, BST1, GAK, LRRK2, PARK16, FGF20, STX1B, and STBD1. In view of their small effect sizes (odds ratio <1.5), genetic variants within these loci are unlikely to be causative. However, further characterization of these loci may lead to the identification of novel molecular risk factors for PD. The reported association between PD risk and variants in SNCA warrants particular attention. This gene encodes alpha-synuclein, which is the main component of the pathological hallmark of PD, the Lewy body. Mutations in SNCA have also been found in familial forms of the disease. Hence, evidence exists for the presence of common pathological mechanisms for familial and complex PD. In addition, research has confirmed that the genetic association with SNCA is present in different ethnic groups, thus indicating that SNCA plays a central role in the etiology of PD across populations. For other PD loci, the variant originally associated with PD in the discovery population showed no cross-population effect. This was the case for variants in the PD loci, BST1 and PARK16, both of which showed association in the Japanese population. However, the association with these two PD loci has since been reported in Caucasian GWASs. To provide an explanation for these discrepant findings across populations, Li et al. investigated regional differences in linkage disequilibrium (LD) patterns in PARK16 by evaluating the extent of LD variation in various ethnic groups (Li et al. current issue of Movement Disorders). LD refers to the tendency of alleles at adjacent loci to be inherited together. This tendency varies between populations, and this may explain the initial lack of association (lack of transferability) reported for some original GWAS single-nucleotide polymorphisms (SNPs) at PARK16 in Caucasian PD cohorts (Fig. 1A). However, this is not the only potential explanation. An alternative hypothesis is that different populations have different causative variants at any given risk locus. In this scenario, associated variants from a GWAS in one population only provide information for causative variants in this one particular population, and not for causative variants in a second population. In either case, the information obtained from the strategy of Li et al. will be pivotal in terms of identifying SNPs that can be used for replication in the same population, or for transferability studies in different populations. In the scenario of differing LD segments across populations, the work of Li et al. will provide information on which SNP is better suited for transferability experiments. In the scenario of differing causative variants at a given locus in different populations, additional variants will be required to cover the associated gene or region. Here, several factors will influence the number of explored variants, including their location in coding or promoter regions, low levels of LD in the population of interest, marker -----------------------------------------------------------*Correspondence to: Dr. Alfredo Ramirez, Department of Psychiatry and Psychotherapy, University of Bonn, Sigmund Freud-Strasse 25, D-53127 Bonn, Germany; alfredo.ramirez@ukb.uni-bonn.de