Neurodegenerative and neuropsychiatric disorders are pervasive and debilitating conditions characterized by diverse clinical syndromes and comorbidities, whose origins are as complex and heterogeneous as their associated phenotypes. Risk for these disorders involves substantial genetic liability, which has fueled large-scale genetic studies that have led to a flood of discoveries. In turn, these discoveries have exposed substantial gaps in our knowledge with regards to the complicated genetic architecture of each disorder and the substantial amount of genetic overlap among disorders, which implies some degree of shared pathophysiology underlying these clinically distinct, multifactorial disorders. Understanding the role of specific genetic variants will involve resolving the connections between molecular pathways, heterogeneous cell types, specific circuits and disease pathogenesis at the tissue and patient level. We consider the current known genetic basis of these disorders and highlight the utility of molecular systems approaches that establish the function of genetic variation in the context of specific neurobiological networks, cell-types, and life stages. Beyond expanding our knowledge of disease mechanisms, understanding these relationships provides promise for early detection and potential therapeutic interventions.

神经退行性疾病和神经精神疾病是一种普遍存在且令人衰弱的疾病，其特征是多种临床综合征和合并症，其起源与其相关表型一样复杂和异质。这些疾病的风险涉及大量的遗传责任，这推动了大规模的遗传研究，并带来了大量的发现。反过来，这些发现暴露了我们对每种疾病的复杂遗传结构和疾病之间大量遗传重叠的认识存在巨大差距，这意味着这些临床上独特的多因素疾病背后存在某种程度的共同病理生理学。了解特定遗传变异的作用将涉及解决组织和患者水平的分子途径、异质细胞类型、特定回路和疾病发病机制之间的联系。我们考虑了这些疾病目前已知的遗传基础，并强调了分子系统方法的实用性，这些方法在特定的神经生物学网络、细胞类型和生命阶段的背景下建立遗传变异的功能。除了扩大我们对疾病机制的了解之外，了解这些关系还为早期检测和潜在的治疗干预提供了希望。