Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1p = 4 × 10⁻¹⁷), arthritis (GDF5p = 4 × 10⁻¹³), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing.

Arachnoid granulations (AG) are poorly investigated. Historical reports suggest that they regulate brain volume by passively transporting cerebrospinal fluid (CSF) into dural venous sinuses. Here, we studied the microstructure of cerebral AG in humans with the aim of understanding their roles in physiology. We discovered marked variations in AG size, lobation, location, content, and degree of surface encapsulation. High-resolution microscopy shows that AG consist of outer capsule and inner stromal core regions. The fine and porous framework suggests uncharacterized functions of AG in mechanical CSF filtration. Moreover, internal cytokine and immune cell enrichment imply unexplored neuroimmune properties of these structures that localize to the brain–meningeal lymphatic interface. Dramatic age-associated changes in AG structure are additionally identified. This study depicts for the first time microscopic networks of internal channels that communicate with perisinus spaces, suggesting that AG subserve important functions as transarachnoidal flow passageways. These data raise new theories regarding glymphatic–lymphatic coupling and mechanisms of CSF antigen clearance, homeostasis, and diseases.

Previous genome-wide association studies (GWAS) have identified potential genetic variants associated with the risk of major depressive disorder (MDD), but the underlying biological interpretation remains largely unknown. We aimed to prioritize genes that were pleiotropically or potentially causally associated with MDD. We applied the summary data-based Mendelian randomization (SMR) method integrating GWAS and gene expression quantitative trait loci (eQTL) data in 13 brain regions to identify genes that were pleiotropically associated with MDD. In addition, we repeated the analysis by using the meta-analyzed version of the eQTL summary data in the brain (brain-eMeta). We identified multiple significant genes across different brain regions that may be involved in the pathogenesis of MDD. The prime-specific geneBTN3A2(corresponding probe: ENSG00000186470.9) was the top hit showing pleiotropic association with MDD in 9 of the 13 brain regions and in brain-eMeta, after correction for multiple testing. Many of the identified genes are located in the human major histocompatibility complex (MHC) region on chromosome 6 and are mainly involved in the immune response. Our SMR analysis indicated that multiple genes showed pleiotropic association with MDD across the brain regions. These findings provided important leads to a better understanding of the mechanism of MDD and revealed potential therapeutic targets for the prevention and effective treatment of MDD.