An estimate of amyotrophic lateral sclerosis heritability using twin data

A Al-Chalabi; F Fang; M F Hanby; P N Leigh; C E Shaw; W Ye; F Rijsdijk

doi:10.1136/jnnp.2010.207464

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An estimate of amyotrophic lateral sclerosis heritability using twin data

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Possibility of epigenetic events in the pathogenesis of ALS
Heikki Savolainen
Published on: 13 April 2016
Re:Possibility of epigenetic events in the pathogenesis of ALS
Ammar Al-Chalabi
Published on: 13 April 2016
Possibility of epigenetic events in the pathogenesis of ALS
Heikki Savolainen
Published on: 13 April 2016

Published on: 13 April 2016
Possibility of epigenetic events in the pathogenesis of ALS
- Heikki Savolainen, Prof.
Dear Editor,
The twin studies show conclusively the limits of classical genetics in the studies of the etiology and pathogenesis of the ALS (1).
It has been suggested that a susceptibility or familial factor could play a role. In this case, they may be mediated by epigenetic mechanisms which control the activity and expression of the genome (2).
The incorrectly coded polypeptides could lead to...
Show More

Dear Editor,
The twin studies show conclusively the limits of classical genetics in the studies of the etiology and pathogenesis of the ALS (1).
It has been suggested that a susceptibility or familial factor could play a role. In this case, they may be mediated by epigenetic mechanisms which control the activity and expression of the genome (2).
The incorrectly coded polypeptides could lead to a gain of function of an enzyme or to aberrant tertiary structures of protein species (3).
This sequence of events could also shed light on familial cases as family members often are exposed to similar environment or other exogenous factors.
1 Al-Chalabi A, Fang F, Leigh PN, et al. An estimate of amytotrophic lateral sclerosis heritability using twin data. J Neurol Neurosurg Psychiatry 2010; 81: 1324-1326
2 Stauffer BL, DeSouza CA. Epigenetics: an emerging player in health and disease. J appl Physiol 2010; 109: 230-231
3 Palo J, Savolainen H, Kivalo E. Comparison between the proteins of human brain myelin in subacute sclerosing panencephalitis, amyotrophic lateral sclerosis and malignant diseases. J neurol Sci 1973; 18: 175-181
Conflict of Interest:
None declared
Show Less

Conflict of Interest:
None declared.
- Back to top
Published on: 13 April 2016
Re:Possibility of epigenetic events in the pathogenesis of ALS
- Ammar Al-Chalabi, Neurology and Genetics
Dear Editor,
We agree that genetic studies have so far explained only a small fraction of the heritability of ALS (1,2), and this is true in many other diseases as well (3). Epigenetic factors are almost certainly part of the answer, but there are also several other possibilities. We are only just developing the tools to look for disease-associated rare variants on a large scale. In addition, we do not understa...
Show More

Dear Editor,
We agree that genetic studies have so far explained only a small fraction of the heritability of ALS (1,2), and this is true in many other diseases as well (3). Epigenetic factors are almost certainly part of the answer, but there are also several other possibilities. We are only just developing the tools to look for disease-associated rare variants on a large scale. In addition, we do not understand the genetic code for most of the genome since we can only reliably translate the 1% that is exonic sequence (4). This means much variation cannot be interpreted even though it is very likely to contribute to disease and the associated genetic variants may be weak correlates of the larger effect true causal variant. We do not routinely search for interaction between genes or genes and environment and there is no easy method to interpret the actions of multiple gene variants acting in concert. Furthermore, the three dimensional nature of the genome is not considered but may have a role to play in disease if variants in physical proximity interact through protein binding or other mechanisms.
As genetic, statistical and computing technologies advance, we expect our current linear and simple view of the genome to be transformed and far more of the so-called missing heritability explained.
(1) Al-Chalabi A, Fang F, Leigh PN, et al. An estimate of amytotrophic lateral sclerosis heritability using twin data. J Neurol Neurosurg Psychiatry 2010;81:1324-1326
(2) Shatunov A, Mok K, Newhouse S, et al. Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the UK and seven other countries: a genome-wide association study. Lancet Neurol 2010;9,986-994
(3) Manolio TA, Collins FS, Cox NJ, et al. Finding the missing heritability of complex diseases. Nature 2009;461,747-753
(4) Taft RJ, Pheasant M, and Mattick JS. The relationship between non -protein-coding DNA and eukaryotic complexity. Bioessays 2007;29:288-299
Conflict of Interest:
None declared
Show Less

Conflict of Interest:
None declared.
- Back to top
Published on: 13 April 2016
Possibility of epigenetic events in the pathogenesis of ALS
- Heikki Savolainen, Prof.
Dear Editor,
The twin studies show conclusively the limits of classical genetics in the studies of the etiology and pathogenesis of the ALS (1).
It has been suggested that a susceptibility or familial factor could play a role. In this case, they may be mediated by epigenetic mechanisms which control the activity and expression of the genome (2).
The incorrectly coded polypeptides could lead to...
Show More

Dear Editor,
The twin studies show conclusively the limits of classical genetics in the studies of the etiology and pathogenesis of the ALS (1).
It has been suggested that a susceptibility or familial factor could play a role. In this case, they may be mediated by epigenetic mechanisms which control the activity and expression of the genome (2).
The incorrectly coded polypeptides could lead to a gain of function of an enzyme or to aberrant tertiary structures of protein species (3).
This sequence of events could also shed light on familial cases as family members often are exposed to similar environment or other exogenous factors.
1 Al-Chalabi A, Fang F, Leigh PN, et al. An estimate of amytotrophic lateral sclerosis heritability using twin data. J Neurol Neurosurg Psychiatry 2010; 81: 1324-1326
2 Stauffer BL, DeSouza CA. Epigenetics: an emerging player in health and disease. J appl Physiol 2010; 109: 230-231
3 Palo J, Savolainen H, Kivalo E. Comparison between the proteins of human brain myelin in subacute sclerosing panencephalitis, amyotrophic lateral sclerosis and malignant diseases. J neurol Sci 1973; 18: 175-181
Conflict of Interest:
None declared
Show Less

Conflict of Interest:
None declared.
- Back to top

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