Genome-wide homozygosity and multiple sclerosis in Orkney and Shetland Islanders

Abstract

There is strong evidence for both genetic and environmental risk factors comprising the aetiology of multiple sclerosis (MS). While much progress has been made in recent years in identifying common genetic variants using genome-wide association studies, alternative approaches have remained relatively neglected. The prevalence of MS in Orkney and Shetland is among the highest in the world. Previous studies have suggested that a higher degree of parental relatedness in these isolated communities may contribute to the high rates of MS, indicating that recessive effects have an important role in MS aetiology. The Northern Isles Multiple Sclerosis (NIMS) study investigated the potential role of genome-wide homozygosity in MS risk by genotyping 88 MS patients, 89 controls matched by age, sex and ancestry, and a further 89 controls matched for sex and ancestry, but passed the majority of lifetime risk of developing MS (470 years of age). Three participants were removed on the basis of pedigreegenomic anomalies (n¼263). Three measures of genome-wide homozygosity were generated for each individual, and association with MS was assessed using logistic regression models. No effect of genome-wide homozygosity was detected, indicating that inbreeding and consanguinity are not risk factors for MS in this population.

High inbreeding in the Faroe Islands does not appear to constitute a risk factor for multiple sclerosis

“…However, it could be a true difference between the populations. McWhirther et al 19 found a mean pair-wise kinship (pi-hat) of 0.004 in their Orkney and Shetland sample whereas it was 0.01697 in our population sample. Furthermore, the observed number of homozygotes was also greater in our sample indicating that the population of the Faroe Islands are more closely related than those of the Orkney and Shetland Islands.…”

“…It is an estimate of the size of an individual's recent and ancient ancestral gene pool. 19 2) Number of ROHs at the following lengths ≥1 mega base pairs (Mb), ≥1.5 Mb, ≥2.5 Mb and ≥5 Mb. Short ROHs are found in all populations, whereas long ROHs are almost only seen in more isolated populations.…”

“…19 Whereas observed number of homozygotes takes into account both ancient and recent ancestral history, ROH is a measurement of an individual's more recent ancestral gene pool. 19 In this analysis cases had a greater number of ROHs than controls; however, the difference only reached significance at ROH ≥ 2.5 MB. Thus an important point to consider is that although cases do not appear to be more inbred that controls based on observed number of homozygotes and inbreeding factors, cases might still differ from controls at a more recent ancestral level in another way than inbreeding, resulting in cases conserving a greater number of ROHs.…”

A new prevalence study of multiple sclerosis in Orkney, Shetland and Aberdeen city

“…In cases of doubt, a senior neurologist made the final decision. Some patients (n=81) taking part in a parallel genetics study19 were examined by the research fellow. We recorded the subtype of MS (relapse–remitting, secondary progressive and primary progressive), and disability status was scored using a modified Expanded Disability Status Scale (EDSS)20 (mild 0–2.5, mild to moderate 3–5.5, moderate to severe 6–7.5 and severe 8–9.5) estimated from the patient records.…”

Patterns of homozygosity in insular and continental goat breeds

“…Geographic isolation of populations may lead to a considerable loss of diversity, an increase in inbreeding and vulnerability to stochastic events [ 6 ]. For instance, human populations with a history of prolonged isolation on the Orkney or Dalmatian Islands or in Sardinia have longer ROH than continental populations, which indicates an elevated relatedness [ 7 , 8 ]. A high frequency of ROH can have detrimental effects on biological fitness and reproductive success because ROH are often enriched in deleterious mutations [ 9 ].…”