Case-Control Studies Are Not Familial Studies

Wang, Zhe; Sadovnick, A. Dessa; Traboulsee, Anthony; Ross, Jay P.; Bernales, Cecily Q.; Encarnacion, Mary Joy; Yee, Irene M.; Lemos, Madonna de; Greenwood, Talitha; Lee, Joshua D.; Wright, Galen E.B.; Ross, Colin J.; Zhang, Si; Song, Weihong; Vilariño‐Güell, Carles

doi:10.1016/j.neuron.2016.09.053

Cited by 12 publications

(7 citation statements)

References 29 publications

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“…Although no unrelated healthy controls were found to harbor RNF213 p.Asn2327Asp in our cohort, this substitution has been observed in populations of European descent with a MAF of 0.13% [17]. Although the data from this publicly available database has been generated primarily from diseased individuals, not healthy controls, and from a locale geographically distinct to our MS cohort [96]; it suggests that RNF213 p.Asn2327Asp is a risk factor for MS, with carriers having more than twice the risk of developing disease (OR = 2.07; 95% CI = 1.15–3.72).…”

Section: Resultsmentioning

confidence: 99%

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Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease

et al. 2019

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Multiple sclerosis (MS) is an inflammatory disease of the central nervous system characterized by myelin loss and neuronal dysfunction. Although the majority of patients do not present familial aggregation, Mendelian forms have been described. We performed whole-exome sequencing analysis in 132 patients from 34 multi-incident families, which nominated likely pathogenic variants for MS in 12 genes of the innate immune system that regulate the transcription and activation of inflammatory mediators. Rare missense or nonsense variants were identified in genes of the fibrinolysis and complement pathways ( PLAU , MASP1 , C2 ), inflammasome assembly ( NLRP12 ), Wnt signaling ( UBR2 , CTNNA3 , NFATC2 , RNF213 ), nuclear receptor complexes ( NCOA3 ), and cation channels and exchangers ( KCNG4 , SLC24A6 , SLC8B1 ). These genes suggest a disruption of interconnected immunological and pro-inflammatory pathways as the initial event in the pathophysiology of familial MS, and provide the molecular and biological rationale for the chronic inflammation, demyelination and neurodegeneration observed in MS patients.

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Section: Resultsmentioning

confidence: 99%

“…In addition, LXR-α which is encoded by NR1H3 , was found to harbor a rare p.Arg415Gln mutation co-segregating with MS in two multi-incident families, and common alleles resulting in increased disease susceptibility [9]. Although this association was initially controversial [96, 111], it has now been independently replicated [6, 112].…”

Section: Resultsmentioning

confidence: 99%

Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease

et al. 2019

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“…This Matters Arising paper is in response to Wang et al (2016a), published in Neuron . See also the related Matters Arising paper by Minikel and MacArthur (2016) and the response by Wang et al (2016b), published in this issue. …”

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NR1H3 p.Arg415Gln Is Not Associated to Multiple Sclerosis Risk

Antel¹,

Ban²,

Baranzini³

et al. 2016

Neuron

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SUMMARY A recent study by Wang et al. (2016a) claims that the low-frequency variant NR1H3 p.Arg415Gln is sufficient to cause multiple sclerosis in certain individuals and determines a patient’s likelihood of primary progressive disease. We sought to replicate this finding in the International MS Genetics Consortium (IMSGC) patient collection, which is 13-fold larger than the collection of Wang et al. (2016a), but we find no evidence that this variant is associated with either MS or disease subtype. Wang et al. (2016a) also report a common variant association in the region, which we show captures the association the IMSGC reported in 2013. Therefore, we conclude that the reported low-frequency association is a false positive, likely generated by insufficient sample size. The claim of NR1H3 mutations describing a Mendelian form of MS—of which no examples exist—can therefore not be substantiated by data. This Matters Arising paper is in response to Wang et al. (2016a), published in Neuron. See also the related Matters Arising paper by Minikel and MacArthur (2016) and the response by Wang et al. (2016b), published in this issue.

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“…They are also characterized by greater genetic homogeneity between individuals, and enable a better understanding of associated autoimmunity. However, they also involve certain disadvantages, such as small sample sizes (Wang et al, ) and reduced statistical power when analysing the cohort as a whole. Analysis of whole families, as performed in the present study rather than trios (comparing patients to first‐degree relatives), increases the power of family studies.…”

Section: Discussionmentioning

confidence: 99%

Exonic variants of genes related to the vitamin D signaling pathway in the families of familial multiple sclerosis using whole‐exome next generation sequencing

et al. 2019

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Introduction Vitamin D (VD) deficiency has been associated with multiple sclerosis (MS) and other autoimmune diseases (AIDs). However, the effect of the genetics of VD on the risk of MS is subject to debate. This study focuses on genes linked to the VD signaling pathway in families with MS. The evaluation of gene variants in all the members of families could contribute to an additional knowledge on the information obtained from case‐control studies that use nonrelated healthy people. Material and Methods We studied 94 individuals from 15 families including at least two patients with MS. We performed whole‐exome next generation sequencing on all individuals and analyzed variants of the DHCR7, CYP2R1, CYP3A4, CYP27A1, GC, CYP27B1, LRP2, CUBN, DAB2, FCGR, RXR, VDR, CYP24A1, and PDIA3 genes. We also studied PTH, FGF23, METTL1, METTL21B, and the role of the linkage disequilibrium block on the long arm of chromosome 12, through analysis of the CDK4, TSFM, AGAP2, and AVIL genes. We compared patients with MS, other AIDs and unaffected members from different family types. Results The study described the variants in the VD signaling pathway that appear in families with at least two patients with MS. Some infrequent variants were detected in these families, but no significant difference was observed between patients with MS and/or other AIDs and unaffected family members in the frequency of these variants. Variants previously associated with MS in the literature were not observed in these families or were distributed similarly in patients and unaffected family members. Conclusion The study of genes involved in the VD signaling pathway in families that include more than one patient with MS did not identify any variants that could explain the presence of the disease, suggesting that VD metabolism could probably play a role in MS more as an environmental factor rather than as a genetic factor. Our study also supports the analysis of cases and unaffected individuals within families in order to determine the influence of genetic factors.

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Case-Control Studies Are Not Familial Studies

Cited by 12 publications

References 29 publications

Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease

Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease

NR1H3 p.Arg415Gln Is Not Associated to Multiple Sclerosis Risk

Exonic variants of genes related to the vitamin D signaling pathway in the families of familial multiple sclerosis using whole‐exome next generation sequencing

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