Title: The Causal Impact of Genetically Predicted Inflammatory Bowel Disease on
Extraintestinal Manifestations: A Mendelian Randomization Study
Version: 4 Date: 13 Oct 2024
Reviewer's report:
This paper has used sophisticated statistical methodology to address the contribution of genetic
factors tors known to be associated with inflammatory bowel disease to assess their influence
on the development of extra-intestinal clinical manifestations already suspected of being
associated with inflammatory bowel disease from n numerous other studies. They describe
the use of Mendelian randomisation as an alternative to randomised controlled clinical trials
to assess the impact of various SNPs associated with IBD on the development of extra-
intestinal manifestations, concluding that genes involved in IBD also contribute significantly to
uveitis, erythema nodosum and sclerosis cholangitis. They also claim to demonstrate that genes
associated with IBD do not appear to influence the development of scleritis/episcleritis. This
type of meta-analysis has the potential to develop great power to detect such genetic effects but
is heavily dependent on the genetic homogeneity  of the study groups. By their own admission
this analysis is heavily weighted of 5th presence of Finnish data sets among the "European"
samples. In the remaining non-Finnish samples there is also considerable heterogeneity. To label
the sample sets as European is disingenuous. There is very considerable genetic variation within
Europe. In the case of the Finnish population there is substantial evidence of a population bottle
neck reflecting the migration. of this population from southern Europe (roughly where Hungary
is now) about 1,000 years ago. Even in the British Isles one would be suspicious about using a
control sample from the south of UK to compare with a disease sample from the north of the
country since there are well described gradients. thus although the results in relation to uveitis,
sclerosis cholesterol;angitis and erythema nodosum are unsurprising I do not feel that the sample
populations are necessarily homogeneous enough to justify definite conclusions to be drawn
about the lack of association with scleritis. Only by altering the selection of the sample groups
to include more genetically homogeneous populations can this deficiency be overcome. Sine
the authors have drawn on published data perhaps it would be worth trying to draw on other
published data including only those results from populations that exhibit more homogeneity.
Title: The Causal Impact of Genetically Predicted Inflammatory Bowel Disease on
Extraintestinal Manifestations: A Mendelian Randomization Study
Version: 4 Date: 13 Oct 2024
Reviewer's report:
This paper has used sophisticated statistical methodology to address the contribution of genetic
factors tors known to be associated with inflammatory bowel disease to assess their influence
on the development of extra-intestinal clinical manifestations already suspected of being
associated with inflammatory bowel disease from n numerous other studies. They describe
the use of Mendelian randomisation as an alternative to randomised controlled clinical trials
to assess the impact of various SNPs associated with IBD on the development of extra-
intestinal manifestations, concluding that genes involved in IBD also contribute significantly to
uveitis, erythema nodosum and sclerosis cholangitis. They also claim to demonstrate that genes
associated with IBD do not appear to influence the development of scleritis/episcleritis. This
type of meta-analysis has the potential to develop great power to detect such genetic effects but
is heavily dependent on the genetic homogeneity  of the study groups. By their own admission
this analysis is heavily weighted of 5th presence of Finnish data sets among the "European"
samples. In the remaining non-Finnish samples there is also considerable heterogeneity. To label
the sample sets as European is disingenuous. There is very considerable genetic variation within
Europe. In the case of the Finnish population there is substantial evidence of a population bottle
neck reflecting the migration. of this population from southern Europe (roughly where Hungary
is now) about 1,000 years ago. Even in the British Isles one would be suspicious about using a
control sample from the south of UK to compare with a disease sample from the north of the
country since there are well described gradients. thus although the results in relation to uveitis,
sclerosis cholesterol;angitis and erythema nodosum are unsurprising I do not feel that the sample
populations are necessarily homogeneous enough to justify definite conclusions to be drawn
about the lack of association with scleritis. Only by altering the selection of the sample groups
to include more genetically homogeneous populations can this deficiency be overcome. Sine
the authors have drawn on published data perhaps it would be worth trying to draw on other
published data including only those results from populations that exhibit more homogeneity.
Please review this paper.
user
Title: The Causal Impact of Genetically Predicted Inflammatory Bowel Disease on
Extraintestinal Manifestations: A Mendelian Randomization Study
Version: 4 Date: 13 Oct 2024
Reviewer's report:
This paper has used sophisticated statistical methodology to address the contribution of genetic
factors tors known to be associated with inflammatory bowel disease to assess their influence
on the development of extra-intestinal clinical manifestations already suspected of being
associated with inflammatory bowel disease from n numerous other studies. They describe
the use of Mendelian randomisation as an alternative to randomised controlled clinical trials
to assess the impact of various SNPs associated with IBD on the development of extra-
intestinal manifestations, concluding that genes involved in IBD also contribute significantly to
uveitis, erythema nodosum and sclerosis cholangitis. They also claim to demonstrate that genes
associated with IBD do not appear to influence the development of scleritis/episcleritis. This
type of meta-analysis has the potential to develop great power to detect such genetic effects but
is heavily dependent on the genetic homogeneity  of the study groups. By their own admission
this analysis is heavily weighted of 5th presence of Finnish data sets among the "European"
samples. In the remaining non-Finnish samples there is also considerable heterogeneity. To label
the sample sets as European is disingenuous. There is very considerable genetic variation within
Europe. In the case of the Finnish population there is substantial evidence of a population bottle
neck reflecting the migration. of this population from southern Europe (roughly where Hungary
is now) about 1,000 years ago. Even in the British Isles one would be suspicious about using a
control sample from the south of UK to compare with a disease sample from the north of the
country since there are well described gradients. thus although the results in relation to uveitis,
sclerosis cholesterol;angitis and erythema nodosum are unsurprising I do not feel that the sample
populations are necessarily homogeneous enough to justify definite conclusions to be drawn
about the lack of association with scleritis. Only by altering the selection of the sample groups
to include more genetically homogeneous populations can this deficiency be overcome. Sine
the authors have drawn on published data perhaps it would be worth trying to draw on other
published data including only those results from populations that exhibit more homogeneity.
assistant