title: Case-Control Studies Are Not Familial Studies.
abstract: Identifying rare genetic variants that drive the onset of disease is challenging, even before considering the additional genetic and environmental influences that likely exist in complex diseases. We recently published a study proposing a rare variant in the NR1H3 gene (p.R415Q, rs61731956) as responsible for the onset of multiple sclerosis (MS) in two multi-incident families (Wang et al., 2016). This publication has generated much discussion, and fortunately the possibility to validate a finding or prove it spurious can occur rapidly in genetic studies. All novel discoveries must be replicated, and best efforts should be made to ensure that these replications use the appropriate samples and approach, and provide the correct interpretation of the results. This Matters Arising Response paper addresses the Minikel and MacArthur (2016) and The International Multiple Sclerosis Genetics Consortium (2016) Matters Arising papers, published concurrently in Neuron.
authors.affiliation: Townsend Family Laboratories, Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; Division of Neurology, Faculty of Medicine, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: A Dessa
authors.initials: AD
authors.lastname: Sadovnick
authors.affiliation: Division of Neurology, Faculty of Medicine, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Traboulsee
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Jay P
authors.initials: JP
authors.lastname: Ross
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Cecily Q
authors.initials: CQ
authors.lastname: Bernales
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Mary
authors.initials: M
authors.lastname: Encarnacion
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Irene M
authors.initials: IM
authors.lastname: Yee
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Madonna
authors.initials: M
authors.lastname: de Lemos
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Talitha
authors.initials: T
authors.lastname: Greenwood
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Lee
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Galen
authors.initials: G
authors.lastname: Wright
authors.affiliation: Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Ross
authors.affiliation: Townsend Family Laboratories, Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Si
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Townsend Family Laboratories, Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Weihong
authors.initials: W
authors.lastname: Song
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z4, Canada. Electronic address: carles@can.ubc.ca.
authors.forename: Carles
authors.initials: C
authors.lastname: Vilariño-Güell
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D009103:Multiple Sclerosis / Q000235:genetics