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Objective: To study whether the risk of amyotrophic lateral sclerosis (ALS) is increased in people with prior autoimmune disease., Methods: An all-England hospital record-linkage dataset spanning 1999-2011 was used. Cohorts were constructed of people with each of a range of autoimmune diseases; the incidence of ALS in each disease cohort was compared with the incidence of ALS in a cohort of individuals without prior admission for the autoimmune disease., Results: There were significantly more cases than expected of ALS associated with a prior diagnosis of asthma, celiac disease, younger-onset diabetes (younger than 30 years), multiple sclerosis, myasthenia gravis, myxedema, polymyositis, Sjögren syndrome, systemic lupus erythematosus, and ulcerative colitis., Conclusions: Autoimmune disease associations with ALS raise the possibility of shared genetic or environmental risk factors.

Background: Multiple sclerosis (MS) is a disease that is widely believed to be autoimmune in nature. Genetic-epidemiological studies implicate susceptibility genes in the pathogenesis of MS, although non-MHC susceptibility linkages have been difficult to confirm. Insight into pathways that are intrinsic to other complex diseases has come from the genetic analysis of large, autosomal-dominant kindreds. Here, we present a genetic study of a large and unique kindred in which MS appears to follow an autosomal-dominant pattern of inheritance, with consistent penetrance in four generations. Methods: Eighty-two individuals of this 370-member family were genotyped with 681 microsatellite markers spanning the genome, with an average spacing of 5.3 cM. Results: Parametric linkage analysis was performed and no significant LOD score (LOD >3.3) was observed. For a rare dominant disease model with reduced penetrance, 99.6% of the genome was excluded at a LOD score <-1 and 96% at a LOD score <-2. The HLA-DRB1 candidate gene was also genotyped by allele-specific methods. In each instance where at least one parent was positive for HLA-DRB1*15, one or more HLA-DRB1*15 alleles were transmitted to the affected offspring )1 1/1 1). HLA- DRB1*15 was transmitted equally from both the familial and the married-in parents and therefore this locus does not appear to be an autosomal-dominant acting gene in this family but an important modifier of risk. Conclusions: These results further stress the importance of the HLA-DRB1 *15-bearing haplotype in determining MS susceptibility. Furthermore, this study highlights the complexity of MS genetics, even in the presence of a single family, seemingly segregating MS as an autosomal-dominant trait. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an autoimmune disease with overwhelming evidence for genetic determination, and for which a maternal parent-of-origin effect has been reported. As with many complex diseases, multiple suggestive linkage signals have been observed. However, the only unambiguous association and linkage identified to date is with alleles of the human lymphocyte antigen (HLA) class II region. We have now carried out high-density microsatellite genotyping for 12 of the most promising regions (1p, 1q, 2q, 4q, 5p, 9q, 10p, 11p, 12q, 17q, 18p, 19p) from a whole-genome scan in 552 affected sibling pairs. This has been carried out in 194 families containing avuncular pairs. These permit examination of parent-of-origin effects in non-colineal pairs when divided into likely maternal and paternal trait transmission. The results do not confirm any non-major histocompatibility complex linkage in the overall subset nor in the maternal, paternal or HLA-DRB1*1501 subsets. We were able to establish exclusion for a locus with λAV1.3 for all the previously suggested regions. These results again raise the possibility that the paradigm of multiple genes of small individual effect used to justify genome searches in MS is incorrect.Genes and Immunity (2006) 7, 366–371. doi:10.1038/sj.gene.6364308; published online 1 June 2006 [ABSTRACT FROM AUTHOR]