Shared loci of telomere length with brain morphology, and pleiotropy in transcriptomic and epigenomic profiles of brain

Abstract

Premature shortening of telomere length is observed in neuropsychiatric disorders. We tested genetic colocalization of seven and nine leukocyte telomere length (LTL) loci in two ancestry groups, European (EUR) and East-Asian (EAS), respectively (total n=60,601) with brain morphology measures for 101 region-of-interests (ROI) (n=21,821). The posterior probability (>90%) was observed for fourth ventricle, gray matter and cerebellar vermal lobules I-IV volumes. We found regulatory genes (p [≤]2.47 x10-6) by integrating transcriptomic (EAS=4;EUR=5) and methylation data (EUR=17; EAS=4) of brain tissues using Summary-based Mendelian Randomization (SMR). The LTL SNP associations were tested for brain-based chromatin profiles using H-MAGMA (EUR=50; EAS=97; p [≤] 1.02 x10-6). Pathway enrichment of tissue-specific genes highlighted calcium ion transport (fetal brain) and G2/M cell cycle transition (adult brain). This study provides evidence that previously reported LTL associations with neuropsychiatric disorders could be related to a shared genetic relationship between LTL and brain structural and regulatory traits.