Nils Eiel Steen | Search PubMed

PubMed2025

A genome-wide analysis of the shared genetic risk architecture of complex neurological and psychiatric disorders.

Although neurological and psychiatric disorders have historically been considered to reflect distinct pathogenic entities, recent findings suggest shared pathophysiological mechanisms. However, the extent to which these heritable disorders share genetic influences remains unclear. Here we performed a comprehensive analysis of genome-wide association study data, involving nearly 1 million cases across ten neurological diseases and ten psychiatric disorders, to compare their common genetic signal and biological associations. Using complementary statistical tools, we demonstrate that a large set of common genetic variants impacts the risk of multiple neurological and psychiatric disorders, even in the absence of genetic correlations. Furthermore, genome-wide association studies on psychiatric disorders consistently implicate neuronal biology, whereas neurological diseases are associated with diverse neurobiological processes. Together, this study elucidates the genetic relationship between complex neurological and psychiatric disorders, indicating a larger degree of genetic pleiotropy than previously recognized. The findings have implications for disease classification, precision medicine and clinical practice.

Humans↗

PubMed2025

Mapping Cerebellar Morphology in 15q11.2 CNV Carriers Using Normative Modeling.

Copy number variations (CNVs) at the 15q11.2 locus of the human genome have been associated with altered brain structure and increased risk for neurodevelopmental and neuropsychiatric disorders. The cerebellum is increasingly seen as a crucial brain region for neurodevelopmental conditions, yet the effects of 15q11.2 CNVs on cerebellar morphology remain largely unclear. Importantly, 15q11.2 CNVs shows reduced or incomplete penetrance (meaning that not all CNV carriers are affected) and variable expressivity (meaning that symptoms may differ between individuals with the same genetic alteration). Thus, there is a need to not only assess group differences, but also to quantify anatomical variability at the individual level. Here, we address these issues using normative models of brain anatomy trained on large datasets (n > 52k, age range: 3-85) to assess both group and individual-level deviations in cerebellar anatomy in carriers of 15q11.2 deletions (n = 120, mean [SD] age= 64.95 [7.58]) and duplications (n = 149, mean [SD] age=64.31 [7.21]), compared to non-carriers (n = 19,028, mean [SD] age=64.31 [7.58]). Group-level case-control analyses revealed significantly smaller total and regional cerebellar volumes in both deletion and duplication carriers, though with small effect sizes. Individual-level deviation analyses, capturing pronounced alterations in specific individuals, revealed a heterogeneous pattern among carriers. Overall, our findings suggest that CNVs at the 15q11.2 locus exert modest and highly individualized effects on cerebellar morphology.

15q11.2↗