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. 2024 Sep 25;25(19):10317.
doi: 10.3390/ijms251910317.

Are Methylation Patterns in the KALRN Gene Associated with Cognitive and Depressive Symptoms? Findings from the Moli-sani Cohort

Miriam Shasa Quiccione  1 , Alfonsina Tirozzi  1 , Giulia Cassioli  2 , Martina Morelli  1 , Simona Costanzo  1 , Antonietta Pepe  1 , Francesca Bracone  1 , Sara Magnacca  1 , Chiara Cerletti  1 , Danilo Licastro  3 , Augusto Di Castelnuovo  1 , Maria Benedetta Donati  1 , Giovanni de Gaetano  1 , Licia Iacoviello  1   4 , Alessandro Gialluisi  1   4 ; Moli-sani Study Investigators
Affiliations

Are Methylation Patterns in the KALRN Gene Associated with Cognitive and Depressive Symptoms? Findings from the Moli-sani Cohort

Miriam Shasa Quiccione et al. Int J Mol Sci. .

Abstract

The KALRN gene (encoding kalirin) has been implicated in several neuropsychiatric and neurodegenerative disorders. However, genetic evidence supporting this implication is limited and targeted epigenetic analyses are lacking. Here, we tested associations between epigenetic variation in KALRN and interindividual variation in depressive symptoms (PHQ9) and cognitive (MoCA) performance, in an Italian population cohort (N = 2409; mean (SD) age: 67 (9) years; 55% women). First, we analyzed the candidate region chr3:124584826-124584886 (hg38), within the KALRN promoter, through pyrosequencing of 1385 samples. Then, we widened the investigated region by analyzing 137 CpGs annotated to the whole gene, rescued from epigenome-wide (Illumina EPIC) data from 1024 independent samples from the same cohort. These were tested through stepwise regression models adjusted for age, sex, circulating leukocytes fractions, education, prevalent health conditions and lifestyles. We observed no statistically significant associations with methylation levels in the three CpGs tested through pyrosequencing, or in the gene-wide association analysis with MoCA score. However, we observed a statistically significant association between PHQ9 and cg13549966 (chr3:124106738; β (Standard Error) = 0.28 (0.08), Bonferroni-corrected p = 0.025), located close to the transcription start site of the gene. This association was driven by a polychoric factor tagging somatic depressive symptoms (β (SE) = 0.127 (0.064), p = 0.048). This evidence underscores the importance of studying epigenetic variation within the KALRN gene and the role that it may play in brain diseases, particularly in atypical depression, which is often characterized by somatic symptoms.

Keywords: KALRN; MoCA; PHQ9; cognitive performance; depressive symptoms; kalirin.

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Conflict of interest statement

The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
Candidate region analyzed through pyrosequencing. The analyzed chr3:124584826–124584886 (hg38) region—highlighted in green—is reported with (a) a 2 kb and (b) a 200 bp zoom. The picture was created through the UCSC Genome Browser tool (https://genome-euro.ucsc.edu, accessed on 22 January 2024).
Figure 1
Figure 1
Candidate region analyzed through pyrosequencing. The analyzed chr3:124584826–124584886 (hg38) region—highlighted in green—is reported with (a) a 2 kb and (b) a 200 bp zoom. The picture was created through the UCSC Genome Browser tool (https://genome-euro.ucsc.edu, accessed on 22 January 2024).
See this image and copyright information in PMC

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