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Title: Suggestion for linkage of chromosome 1p35.2 and 3q28 to plasma
adiponectin concentrations in the GOLDN Study
Authors:
Laura J Rasmussen-Torvik ([email protected])
James S Pankow ([email protected])
James M Peacock ([email protected])
Ingrid B Borecki ([email protected])
James E Hixson ([email protected])
Michael Y Tsai ([email protected])
Edmond K Kabagambe ([email protected])
Donna K Arnett ([email protected])
Version: 2 Date: 20 February 2009
Author's response to reviews: see over
20 February 09
Dear Dr Norton:
On behalf of Dr. Rasmussen-Torvik and our co-authors, I am submitting a revision of MS:
5741685721821184 “Suggestion for linkage of chromosome 1p35.2 and 3q28 to plasma adiponectin
concentrations in the GOLDN Study” for consideration for publication in BMC Medical Genetics.
We would like to thank the reviewers for their thoughtful comments. We have made many edits in
response to their comments which we believe have improved the manuscript. We have detailed all the
changes we have made below and highlighted all the changes in the text in yellow.
Please contact me at 205-934-7066 or [email protected] if you have any questions.
Sincerely,
Donna K. Arnett, Ph.D.
Corresponding Author
Point-by Point responses
Referee 1:
The very first sentence after the abstract, how can they know this relationship
holds in "most populations",. It seems to me impossible to verify this.
On page 3 line 3 we have changed the first sentence of in background to say the relationship holds in
“several” populations
P7 "... are likely due to subtle differences in population structure ..." there seems
to be no evidence or argument for this being even plausible, let alone "likely".
On page 7, lines 8-12 we have added additional justification for this argument (that baseline and posttrial adiponectin linkage and heritability results were nearly identical in the subset of individuals [n =
859] with both measurements) and tempered our language by indicating the differences “may be due to
subtle differences in population structure.”
P7 "The presence of this significant correlation ... " The existence of a correlation
is not alone sufficient to justify adjustment. SBP and DBP are highly correlated
but it makes no sense to adjust for one when investigating the heritability of the
other. (also two "have" in this sentence).
We have deleted this sentence.
P8 "Rather a pleiotropic gene ...". At least now the authors only say "may", and I
agree that this must be possible. But it seems to be a "rabbit out of a hat",
without explanation of why the evidence points in this direction.
On page 9, lines 11-17 we have changed the text to indicate that this is only 1 of several “possible”
explanations. We have also included a second possible alternate explanation.
P10 "...which may help to decipher true ..." again the "may" saves the authors
from rejecting this claim as false, but there seems no evidence or reason to
believe that this is true. (The claim that I criticise immediately above is, I suspect,
plausible, but this claim isn't; in any case both are unjustified)
We have deleted this sentence.
Minor points:
P6 L-2: if the undesired results were significant it is no help to say that the
studies were small: they can't have been too small to achieve significance (in fact
the unwanted effect sizes must have been large!)
We have deleted this sentence.
Referee 2:
1) The linkage results did not reach genome-wide significance and the two best
results are at most suggestive of linkage; significance of the results should be
estimated genome wise and p-values for the results should be provided (table 3);
in the title, the word “evidence” is not appropriate and should be modified; the
whole discussion should be revised accordingly.
We have changed the title and revised the discussion. Notably, on page 8, lines 7-9 we have indicated
that no areas of linkage reached genome-wide significance. We have also referred to “suggestive” and
“modest” linkage peaks throughout the discussion. We have also added p-values to table 3.
2) In table 3 provide D numbers when available and physical position of the
markers in addition to the p-values;
In addition to p-values we have added D numbers and physical positions to the final column of Table 3.
3) Provide in results the physical position of the -1 LOD support interval on
chromosome 1. Provide the number of known genes lying in this interval and
physical positions of the two candidate genes identified. Cross your peak regions
with data from genome-wide association scans for adiponectin levels such as the
one performed in the Framingham Heart study (data available at
http://www.ncbi.nlm.nih.gov/projects/gap/cgibin/study.cgi?study_id=phs000007.v1.p1);
e.g. a marker rs1288347, located at position 53394681 on chromosome 1 is
potentially associated (p=6.70e-04) and is located in the vicinity of a gene
involved in lipid metabolism.
We have provided the physical positions of the -1 LOD support interval, the number of genes identified,
and the physical positions of the candidate genes on page 6 lines 15-20. We consulted the Framingham
data (no other GWAS on adiponectin have been published to date) and saw no associations in the -1 LOD
interval with a p-value smaller than 10-3.
4) Adiponectin is an obvious candidate gene for the linkage peak on
chromosome 3q. The authors should screen the gene for mutations to evaluate if
the linkage is due to mutations identified in the gene; Guo X reported that
mutations in the adiponectin gene were not responsible for the linkage observed
on chromosome 3q27 and concluded that another gene could be responsible for
modulating the adiponectin levels. On the other hand Pollin TI et coll identified
variations that explained the linkage result.
As we report on pp. 4-5 lines 21-2, page 6 lines 5-11, and page 8 lines 16-21, we typed 2 SNPs in the
ADIPOQ gene and included these SNPs as covariates in additional linkage scans. Although we typed the
SNP most responsible for attenuating linkage in the Pollin paper, our results were more similar to those in
the Guo paper in that we saw little attenuation of the LOD score after adjustment for the SNPs.
5) In discussion on p. 8 (last paragraphs on linkage scans), regarding the “novel
linkages observed on chromosomes 6p23 and 7p14.2”, as mentioned above,
those peaks did not reach genome-wide significance in this study and have never
been identified previously. The most likely explanation is that it is a false positive
result. This possibility should at least be discussed.
On page 10, lines 4-5 we have discussed this possibility.