OBJECTIVE: Multiple sclerosis (MS) is a multifactorial neurologic disease characterized by modest but tractable heritability. Genome-wide association studies have identified and/or validated multiple polymorphisms in approximately 16 genes associated with susceptibility. We aimed at investigating the aggregation of genetic MS risk markers in individuals by comparing multiple- and single-case families. METHODS: A weighted log-additive integrative approach termed MS genetic burden (MSGB) was used to account for the well-established genetic variants from previous association studies and meta-analyses. The corresponding genetic burden and its transmission was analyzed in 1,213 independent MS families (810 sporadic and 403 multicase families). RESULTS: MSGB analysis demonstrated a higher aggregation of susceptibility variants in multicase compared to sporadic MS families. In addition, the aggregation of non-major histocompatibility complex single nucleotide polymorphisms depended neither on gender nor on the presence or absence of HLA-DRB1*15:01 alleles. Interestingly, although a greater MSGB in siblings of MS patients was associated with an increased risk of MS (odds ratio, 2.1; p = 0.001), receiver operating characteristic curves of MSGB differences between probands and sibs (area under the receiver operator curves, 0.57 [95% confidence interval, 0.53-0.61]) show that case-control status prediction of MS cannot be achieved with the currently available genetic data. INTERPRETATION: The primary interest in the MSGB concept resides in its capacity to integrate cumulative genetic contributions to MS risk. This analysis underlines the high variability of family load with known common variants. This novel approach can be extended to other genetically complex diseases. Despite the emphasis on assembling large case-control datasets, multigenerational, multiaffected families remain an invaluable resource for advancing the understanding of the genetic architecture of complex traits.
OBJECTIVE:Multiple sclerosis (MS) is a multifactorial neurologic disease characterized by modest but tractable heritability. Genome-wide association studies have identified and/or validated multiple polymorphisms in approximately 16 genes associated with susceptibility. We aimed at investigating the aggregation of genetic MS risk markers in individuals by comparing multiple- and single-case families. METHODS: A weighted log-additive integrative approach termed MS genetic burden (MSGB) was used to account for the well-established genetic variants from previous association studies and meta-analyses. The corresponding genetic burden and its transmission was analyzed in 1,213 independent MS families (810 sporadic and 403 multicase families). RESULTS: MSGB analysis demonstrated a higher aggregation of susceptibility variants in multicase compared to sporadic MS families. In addition, the aggregation of non-major histocompatibility complex single nucleotide polymorphisms depended neither on gender nor on the presence or absence of HLA-DRB1*15:01 alleles. Interestingly, although a greater MSGB in siblings of MS patients was associated with an increased risk of MS (odds ratio, 2.1; p = 0.001), receiver operating characteristic curves of MSGB differences between probands and sibs (area under the receiver operator curves, 0.57 [95% confidence interval, 0.53-0.61]) show that case-control status prediction of MS cannot be achieved with the currently available genetic data. INTERPRETATION: The primary interest in the MSGB concept resides in its capacity to integrate cumulative genetic contributions to MS risk. This analysis underlines the high variability of family load with known common variants. This novel approach can be extended to other genetically complex diseases. Despite the emphasis on assembling large case-control datasets, multigenerational, multiaffected families remain an invaluable resource for advancing the understanding of the genetic architecture of complex traits.
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Authors: O H Kantarci; L F Barcellos; E J Atkinson; P P Ramsay; R Lincoln; S J Achenbach; M De Andrade; S L Hauser; B G Weinshenker Journal: Neurology Date: 2006-07-25 Impact factor: 9.910
Authors: L F Barcellos; J R Oksenberg; A J Green; P Bucher; J B Rimmler; S Schmidt; M E Garcia; R R Lincoln; M A Pericak-Vance; J L Haines; S L Hauser Journal: Brain Date: 2002-01 Impact factor: 13.501
Authors: Sarah-Michelle Orton; Blanca M Herrera; Irene M Yee; William Valdar; Sreeram V Ramagopalan; A Dessa Sadovnick; George C Ebers Journal: Lancet Neurol Date: 2006-11 Impact factor: 44.182
Authors: B A Johnson; J Wang; E M Taylor; S J Caillier; J Herbert; O A Khan; A H Cross; P L De Jager; P-A F Gourraud; B C A Cree; S L Hauser; J R Oksenberg Journal: Genes Immun Date: 2009-10-29 Impact factor: 2.676
Authors: An Goris; Ine Pauwels; Marte W Gustavsen; Brechtje van Son; Kelly Hilven; Steffan D Bos; Elisabeth Gulowsen Celius; Pål Berg-Hansen; Jan Aarseth; Kjell-Morten Myhr; Sandra D'Alfonso; Nadia Barizzone; Maurizio A Leone; Filippo Martinelli Boneschi; Melissa Sorosina; Giuseppe Liberatore; Ingrid Kockum; Tomas Olsson; Jan Hillert; Lars Alfredsson; Sahl Khalid Bedri; Bernhard Hemmer; Dorothea Buck; Achim Berthele; Benjamin Knier; Viola Biberacher; Vincent van Pesch; Christian Sindic; Annette Bang Oturai; Helle Bach Søndergaard; Finn Sellebjerg; Poul Erik H Jensen; Manuel Comabella; Xavier Montalban; Jennifer Pérez-Boza; Sunny Malhotra; Jeannette Lechner-Scott; Simon Broadley; Mark Slee; Bruce Taylor; Allan G Kermode; Pierre-Antoine Gourraud; Stephen J Sawcer; Bettina Kullle Andreassen; Bénédicte Dubois; Hanne F Harbo Journal: Brain Date: 2015-01-22 Impact factor: 13.501
Authors: Janey L Wiggs; Michael A Hauser; Wael Abdrabou; Robert Rand Allingham; Donald L Budenz; Elizabeth Delbono; David S Friedman; Jae H Kang; Douglas Gaasterland; Terry Gaasterland; Richard K Lee; Paul R Lichter; Stephanie Loomis; Yutao Liu; Cathy McCarty; Felipe A Medeiros; Sayoko E Moroi; Lana M Olson; Anthony Realini; Julia E Richards; Frank W Rozsa; Joel S Schuman; Kuldev Singh; Joshua D Stein; Douglas Vollrath; Robert N Weinreb; Gadi Wollstein; Brian L Yaspan; Sachiko Yoneyama; Don Zack; Kang Zhang; Margaret Pericak-Vance; Louis R Pasquale; Jonathan L Haines Journal: J Glaucoma Date: 2013-09 Impact factor: 2.503
Authors: Noriko Isobe; Anisha Keshavan; Pierre-Antoine Gourraud; Alyssa H Zhu; Esha Datta; Regina Schlaeger; Stacy J Caillier; Adam Santaniello; Antoine Lizée; Daniel S Himmelstein; Sergio E Baranzini; Jill Hollenbach; Bruce A C Cree; Stephen L Hauser; Jorge R Oksenberg; Roland G Henry Journal: JAMA Neurol Date: 2016-07-01 Impact factor: 18.302
Authors: J P McElroy; L B Krupp; B A Johnson; J L McCauley; Z Qi; S J Caillier; P A Gourraud; J Yu; L Nathanson; A L Belman; S L Hauser; E Waubant; D J Hedges; J R Oksenberg Journal: Mult Scler Date: 2012-12-13 Impact factor: 6.312
Authors: Hanne F Harbo; Noriko Isobe; Pål Berg-Hansen; Steffan D Bos; Stacy J Caillier; Marte W Gustavsen; Inger-Lise Mero; Elisabeth Gulowsen Celius; Stephen L Hauser; Jorge R Oksenberg; Pierre-Antoine Gourraud Journal: Mult Scler Date: 2013-10-07 Impact factor: 6.312
Authors: Noriko Isobe; Pierre-Antoine Gourraud; Hanne F Harbo; Stacy J Caillier; Adam Santaniello; Pouya Khankhanian; Martin Maiers; Stephen Spellman; Nezih Cereb; SooYoung Yang; Marcelo J Pando; Laura Piccio; Anne H Cross; Philip L De Jager; Bruce A C Cree; Stephen L Hauser; Jorge R Oksenberg Journal: Neurology Date: 2013-06-14 Impact factor: 9.910