LAUSR

Several studies have reported association between leukocyte telomere length (LTL) and neuropsychiatric disorders. While telomere length is affected by environmental factors, genetic variants in certain loci are strongly associated with LTL. Thus, we aimed to identify the genomic relationship between genetic variants of LTL with brain-based regulatory changes and brain volume. We tested genetic colocalization of seven and nine LTL loci in two ancestry groups, European (EUR) and East-Asian (EAS), respectively with brain morphology measures for 101 T1-MRI based 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 then tested causal relationship using LTL loci for gene and methylation expression. We found causal pleiotropy for gene (EAS = 4 genes; EUR = 5 genes) and methylation expression (EUR = 17 probes; EAS = 4 probes) of brain tissues (p ≤ 2.47 x10-6). Integrating chromatin profiles with LTL-SNPs identified 45 genes (EUR) and 79 genes (EAS) p ≤ 9.78-7. We found additional 38 LTL-genes using chromatin-based gene mapping for EUR ancestry population. Gene variants in three LTL-genes-GPR37, OBFC1, and RTEL1/RTEL1-TNFRSF6B, show convergent evidence of pleiotropy with brain morphology, gene and methylation expression, and chromatin association. Mapping gene functions to drug-gene interactions, we identified process- 'transmission across chemical synapses' (p < 2.78x10-4). This study provides evidence that genetic variants of LTL have pleiotropic roles with brain-based effects that could explain the phenotypic association of LTL with several neuropsychiatric traits.