Genetic analysis of the isolated Faroe Islands reveals SORCS3 as a potential multiple sclerosis risk gene

Abstract

Background:

In search of the missing heritability in multiple sclerosis (MS), additional approaches adding to the genetic discoveries of large genome-wide association studies are warranted.

Objective:

The objective of this research paper is to search for rare genetic MS risk variants in the genetically homogenous population of the isolated Faroe Islands.

Methods:

Twenty-nine Faroese MS cases and 28 controls were genotyped with the HumanOmniExpressExome-chip. The individuals make up 1596 pair-combinations in which we searched for identical-by-descent shared segments using the PLINK-program.

Results:

A segment spanning 63 SNPs with excess case-case-pair sharing was identified (0.00173 < p > 0.00212). A haplotype consisting of 42 of the 63 identified SNPs which spanned the entire the Sortilin-related vacuolar protein sorting 10 domain containing receptor 3 (SORCS3) gene had a carrier frequency of 0.34 in cases but was not present in any controls (p = 0.0008).

Conclusion:

This study revealed an oversharing in case-case-pairs of a segment spanning 63 SNPs and the entire SORCS3. While not previously associated with MS, SORCS3 appears to be important in neuronal plasticity through its binding of neurotrophin factors and involvement in glutamate homeostasis. Although additional work is needed to scrutinise the genetic effect of the SORCS3-covering haplotype, this study suggests that SORCS3 may also be important in MS pathogenesis.

Keywords

Multiple sclerosis genetics inbreeding Faroe Islands risk factors linkage

Get full access to this article

View all access options for this article.

References

Compston

Coles

. Multiple sclerosis. Lancet 2008; 372: 1502–1517.

Hansen

Skytthe

Stenager

. Concordance for multiple sclerosis in Danish twins: An update of a nationwide study. Mult Scler 2005; 11: 504–510.

Westerlind

Boström

Stawiarz

. New data identify an increasing sex ratio of multiple sclerosis in Sweden. Mult Scler 2014; 20: 1578–1583.

Kingwell

Marriott

Jetté

. Incidence and prevalence of multiple sclerosis in Europe: A systematic review. BMC Neurol 2013; 13: 128.

Watson

Disanto

Breden

. Estimating the proportion of variation in susceptibility to multiple sclerosis captured by common SNPs. Sci Rep 2012; 2: 770.

Beecham

Patsopoulos

Xifara

. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat Genet 2013; 45: 1353–1360.

Schork

Murray

Frazer

. Common vs.rare allele hypotheses for complex diseases. Curr Opin Genet Dev 2009; 19: 212–219.

Varilo

Peltonen

. Isolates and their potential use in complex gene mapping efforts. Curr Opin Genet Dev 2004; 14: 316–323.

Kallio

Jakkula

Purcell

. Use of a genetic isolate to identify rare disease variants: C7 on 5p associated with MS. Hum Mol Genet 2009; 18: 1670–1683.

10.

Arcos-Burgos

Muenke

. Genetics of population isolates. Clin Genet 2002; 61: 233–247.

11.

Grant

Thorleifsson

Reynisdottir

. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet 2006; 38: 320–323.

12.

Pajukanta

Lilja

Sinsheimer

. Familial combined hyperlipidemia is associated with upstream transcription factor 1 (USF1). Nat Genet 2004; 36: 371–376.

13.

D’Aoust

Cummings

Laux

. Examination of candidate exonic variants for association to Alzheimer disease in the Amish. PloS One 2015; 10: e0118043.

14.

Helgadottir

Manolescu

Thorleifsson

. The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nat Genet 2004; 36: 233–239.

15.

Jakkula

Leppä

Sulonen

. Genome-wide association study in a high-risk isolate for multiple sclerosis reveals associated variants in STAT3 gene. Am J Hum Genet 2010; 86: 285–291.

16.

Hadjixenofontos

Gourraud

Bakthavachalam

. Enrichment for Northern European-derived multiple sclerosis risk alleles in Sardinia. Mult Scler. 2015; 21: 1369–1403.

17.

Bernardinelli

Murgia

Bitti

. Association between the ACCN1 gene and multiple sclerosis in Central East Sardinia. PloS One 2007; 2: e480.

18.

Hoppenbrouwers

Aulchenko

Ebers

. EVI5 is a risk gene for multiple sclerosis. Genes Immun 2008; 9: 334–337.

19.

Als

Jorgensen

Børglum

. Highly discrepant proportions of female and male Scandinavian and British Isles ancestry within the isolated population of the Faroe Islands. Eur J Hum Genet 2006; 14: 497–504.

20.

Binzer

Imrell

Binzer

. High inbreeding in the Faroe Islands does not appear to constitute a risk factor for multiple sclerosis. Mult Scler 2015; 21: 996–1002.

21.

Jorgensen

Degn

Wang

. Linkage disequilibrium and demographic history of the isolated population of the Faroe Islands. Eur J Hum Genet 2002; 10: 381–387.

22.

Purcell

Neale

Todd-Brown

. PLINK: A tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–575.

23.

Kurtzke

Hyllested

. Multiple sclerosis in the Faroe Islands: I. Clinical and epidemiological features. Ann Neurol 1979; 5: 6–21.

24.

Rasmussen

Nielsen

Janzen

. Carnitine levels in 26,462 individuals from the nationwide screening program for primary carnitine deficiency in the Faroe Islands. J Inherit Metab Dis 2014; 37: 215–222.

25.

Oetjen

Mahlke

Hermans-Borgmeyer

. Spatiotemporal expression analysis of the growth factor receptor SorCS3. J Comp Neurol 2014; 522: 3386–3402.

26.

Reitz

. The role of the retromer complex in aging-related neurodegeneration: A molecular and genomic review. Mol Genet Genomics 2015; 290: 413–427.

27.

Breiderhoff

Christiansen

Pallesen

. Sortilin-related receptor SORCS3 is a postsynaptic modulator of synaptic depression and fear extinction. PloS One 2013; 8: e75006.

28.

Sun

Lehmbecker

Kalkuhl

. STAT3 represents a molecular switch possibly inducing astroglial instead of oligodendroglial differentiation of oligodendroglial progenitor cells in Theiler’s murine encephalomyelitis. Neuropathol Appl Neurobiol 2015; 41: 347–370.

29.

Laudiero

Aloe

Levi-Montalcini

. Multiple sclerosis patients express increased levels of beta-nerve growth factor in cerebrospinal fluid. Neurosci Lett 1992; 147: 9–12.

30.

Rosenberg

Chan

. The quest for remyelination: A new role for neurotrophins and their receptors. Brain Pathol 2006; 16: 288–294.

31.

Westergaard

Kirkegaard

Sørensen

. SorCS3 does not require propeptide cleavage to bind nerve growth factor. FEBS Lett 2005; 579: 1172–1176.

32.

Browning

Thompson

. Detecting rare variant associations by identity-by-descent mapping in case-control studies. Genetics 2012; 190: 1521–1531.

33.

Binzer

Imrell

Binzer

. Multiple sclerosis in a family on the Faroe Islands. Acta Neurol Scand 2010; 121: 16–19.

34.

Howrigan

Simonson

Keller

. Detecting autozygosity through runs of homozygosity: A comparison of three autozygosity detection algorithms. BMC Genomics 2011; 12: 460.

35.

McQuillan

Leutenegger

Abdel-Rahman

. Runs of homozygosity in European populations. Am J Hum Genet 2008; 83: 359–372.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.13 MB