What role for genetics in the prediction of multiple sclerosis
TLDR
For most of us, the foundations of the authors' understanding of genetics were laid by considering Mendelian diseases in which familial recurrence risks are high, and mutant alleles are both necessary and sufficient, but is this the case in complex disease?Abstract:
For most of us, the foundations of our understanding of genetics were laid by considering Mendelian diseases in which familial recurrence risks are high, and mutant alleles are both necessary and sufficient. One consequence of this deterministic teaching is that our conceptualization of genetics tends to be dominated by the notion that the genetic aspects of disease are caused by rare alleles exerting large effects. Unfortunately, the preconceptions that flow from this training are frequently erroneous and misleading in the context of common traits, where familial recurrence risks are modest, and for the most part the relevant alleles are neither rare, necessary, nor sufficient. For these common traits, the genetic architecture is far more complex, with susceptibility rather than causality resulting from the combined effects of many alleles, each exerting only a modest effect on risk. None of these alleles is sufficient to cause disease on its own, and none is essential for the development of disease. Furthermore, most are carried by large sections of the population, the vast majority of which does not develop the disease. One consequence of our innate belief in the Mendelian paradigm is that we have an inherent expectation that knowledge about the genetic basis for a disease should allow genetic testing and thereby accurate risk prediction. There is an inevitable feeling that the same should be true in complex disease, but is it?read more
Citations
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Power and Predictive Accuracy of Polygenic Risk Scores
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Multiple sclerosis genetics.
TL;DR: The functional implications of these associated variants are mostly unknown; however, early work has shown that several variants have effects on splicing that result in meaningful changes in the balance between different isoforms in relevant tissues as discussed by the authors.
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Multiple sclerosis genetics—is the glass half full, or half empty?
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Aggregation of multiple sclerosis genetic risk variants in multiple and single case families
Pierre-Antoine Gourraud,Joseph P. McElroy,Stacy J. Caillier,Britt A. Johnson,Adam Santaniello,Stephen L. Hauser,Jorge R. Oksenberg +6 more
TL;DR: This work aimed at investigating the aggregation of genetic MS risk markers in individuals by comparing multiple‐ and single‐case families.
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Familial effects on the clinical course of multiple sclerosis
Anke Hensiek,S. R. Seaman,L. F. Barcellos,A. Oturai,Mefkure Eraksoy,Eleonora Cocco,László Vécsei,G Steward,Bénédicte Dubois,Judith Bellmann-Strobl,M. Leone,Oluf Andersen,Krisztina Bencsik,David R. Booth,Elisabeth Gulowsen Celius,Hanne F. Harbo,Stephen L. Hauser,Robert Heard,Jan Hillert,Kjell-Morten Myhr,Mg Marrosu,Jorge R. Oksenberg,Cecilia Rajda,Stephen Sawcer,Per Soelberg Sørensen,Frauke Zipp,D. A. S. Compston +26 more
TL;DR: Familial factors do not significantly affect eventual disease severity, however, they increase the probability of a progressive clinical course, either from onset or after a phase of relapsing remitting disease.
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David A. Hafler,Alastair Compston,Stephen Sawcer,Mark J. Daly,Philip L. De Jager,Stacey Gabriel,Daniel B. Mirel,Adrian J. Ivinson,Margaret A. Pericak-Vance,Simon G. Gregory,John D. Rioux,John D. Rioux,Jacob L. McCauley,Lisa F. Barcellos,Lisa F. Barcellos,Bruce A.C. Cree,Stephen L. Hauser +16 more
TL;DR: Alleles of IL2RA and IL7RA and those in the HLA locus are identified as heritable risk factors for multiple sclerosis.
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