Genetic Architecture of Neurological Disorders and Their Endophenotypes: Insights from Genetic Association Studies

Population-scale genetic association studies of complex neurologic diseases have identified the underlying genetic architecture as multifactorial. Despite the study sample sizes reaching the millions, the identified disease-related genes explain only a small fraction of the phenotypic variance. Notable advancements in statistical methods now enable researchers to gain insights even from genomic regions where genotype-phenotype associations do not reach statistical significance. Such studies confirm a highly interconnected molecular network comprising a core group of genes directly involved in the disease process, alongside an expanded peripheral network, each contributing a small but potentially important (modulatory) effect. Additionally, causal inference methods, utilizing genetic instruments, have shed light on putative causal links between risk factors and clinical endpoints. In light of the pervasive genetic overlap or pleiotropy, however, caution is warranted in interpreting causal relationships inferred from these analyses. In this chapter, I will introduce the genetic association model, provide insights into the current state of genetic association studies, and discuss potential future directions.