Deciphering the Effect of Different Genetic Variants on Hippocampal Subfield Volumes in the General Population
, Katharina Wittfeld 1,2, Sabine Ameling 3,4, Robin Bülow 5, Henriette Meyer zu Schwabedissen 6, Matthias Nauck 4,7, Henry Völzke 4,8, Hans J. Grabe 1,2 and Sandra Van der Auwera 1,2,*Round 1
Reviewer 1 Report
This paper tries to assess the effects of distinct genetic factors on specific hippocampal subfield volumes in a large dementia-free cohort of population sample with different approaches. These genetic effects were only studied before in a restricted number of samples with a big heterogeneity.
This study provides a large amount of new genetic information that is contrasted with strong statistical analysis.
Finally, they confirm that some reductions of hippocampal subfield volumes are associated with genetic variants and have an impact on memory performance, especially in older age, in an European cohort population.
Author Response
This paper tries to assess the effects of distinct genetic factors on specific hippocampal subfield volumes in a large dementia-free cohort of population sample with different approaches. These genetic effects were only studied before in a restricted number of samples with a big heterogeneity.
This study provides a large amount of new genetic information that is contrasted with strong statistical analysis.
Finally, they confirm that some reductions of hippocampal subfield volumes are associated with genetic variants and have an impact on memory performance, especially in older age, in an European cohort population.
>> Answer: We thank reviewer 1 for his overall very positive feedback.
Reviewer 2 Report
This is a beautiful study that investigated the effects of various genetic factors on hippocampal subfield volumes by using three different approaches: a biologically driven candidate gene approach, a hypothesis-free GWAS approach, and a polygenic approach where AD risk alleles are combined to a polygenic risk score (PRS). These results are exciting and provide new insights into the biology of hippocampal volume loss, memory impairment, depression and neurodegenerative diseases. In general, the experiments were carefully designed and manuscript is well written, however, some details need to be added. I have only some minor issues that are considered for further improvement.
1. Methods should be more accurately reported in order to describe all the experiments correctly.
2. the authors perform association analyses between hippocampal subfield volumes and memory performance. It would be ideal to include other neurodegenerative diseases samples. At least, the authors should discuss more in the discussion.
Author Response
This is a beautiful study that investigated the effects of various genetic factors on hippocampal subfield volumes by using three different approaches: a biologically driven candidate gene approach, a hypothesis-free GWAS approach, and a polygenic approach where AD risk alleles are combined to a polygenic risk score (PRS). These results are exciting and provide new insights into the biology of hippocampal volume loss, memory impairment, depression and neurodegenerative diseases.
>> Answer: We thank reviewer 2 for his positive feedback on the importance of the analyses. In the next paragraph we try to address the minor issues raised by reviewer 2.
In general, the experiments were carefully designed and manuscript is well written, however, some details need to be added. I have only some minor issues that are considered for further improvement.
- Methods should be more accurately reported in order to describe all the experiments correctly.
>> Answer: We thank reviewer 2 for this comment. In order to better understand the mathematical models and for the aim of replicating our results, we added the mathematical formulas of the statistical models under point 4.4.1 - 4.4.3. If reviewer 2 wants specific points in the methods section to be added, please let us know.
- the authors perform association analyses between hippocampal subfield volumes and memory performance. It would be ideal to include other neurodegenerative diseases samples. At least, the authors should discuss more in the discussion.
>> Answer: We agree with reviewer 2 that a simple association between hippocampal subfields and memory performance is only the basis to analyze specific neurodegenerative disorders in association with hippocampal subfield volume loss. Unfortunately, the SHIP sample is a general population sample without a specific focus on neurodegeneration. The aim of our study was to clarify the associations between genetic factors, verbal memory and hippocampal subfield volumes in a healthy population. These association patterns could be used to form hypothesis for disease populations. To address this point, we added this outlook in the discussion.
“We were able to identify association patterns of individual SNPs that can be linked to biological processes in neurodegeneration already in a relatively healthy and dementia-free population. Whether these patterns can be transferred to disease populations needs to be clarified in independent disease cohorts. Thus, this study underlines the importance of gene-based analyses in the quest for insights into hippocampal volume loss, memory impairment, and neurodegenerative diseases and opens the field for generating hypothesis for neurodegenerative diseases.”
