016-22 – Genome-wide association study of rare variants in HERV-elements of ALS patients: age at onset of ALS may be regulated by MLT1B HERV-element.

The role of human endogenous retroviruses (HERVs) in pathogenesis of neurological and psychiatric diseases has been analysed since the HERV family of transposable elements was discovered and confirmed later for multiple sclerosis and schizophrenia in several studies. Analysis of muscle biopsies and post-mortem brain from patients with amyotrophic lateral sclerosis (ALS) revealed enhanced level of reverse transcriptase activities (a protein encoded by HERVs) in these tissues, suggesting involvement of HERV elements in pathogenesis (Steele et al, 2005). HERV-K and HERV-W were proposed as cause of ALS (Hadlock et al, 2004; Oluwole et al, 2007). It was subsequently demonstrated that HML-2 and 3 subfamilies of HERV-K contributed to development of ALS , by analysis of gene expression of HERV elements in different parts of post-mortem brains of ALS patients (Douville et al, 2011). To investigate the role of HERVs in development of ALS we conducted genome-wide analysis of rare variants on a large ALS-dataset.
Multi-marker variable-threshold analysis have been performed on 6493 ALS patients from the Project Mine NGS dataset. We used age at onset (AAO) as a phenotypic trait in our study to investigate association with rare variants located in HERVs elements. As a bioinformatic tool to conduct association analysis we used rvtests program (Zhan et al., 2016) with famAnalytic option. To correct statistics for type I errors, information on sex, population structure and cryptic relatedness was included in the linear mixed model as additional covariates. Only rare genetic variants with frequencies from 0.000001 to 0.01 were selected for analysis.
We found that a MLT1B HERV element, located in first intron of the UBL3 gene on chromosome 13q12, is associated with AAO trait (P-value = 7.7E-08). The UBL3 gene demonstrated high expression in brain tissues and spinal cord. We speculate that MLT1B potentially can affect age at onset of ALS phenotype by modulating UBL3 expression.