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Epigenome-Wide Exploratory Study of Monozygotic Twins Suggests Differentially Methylated Regions to Associate with Hand Grip Strength

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Epigenome-Wide Exploratory Study of Monozygotic Twins Suggests Differentially Methylated Regions to Associate with Hand Grip Strength Biogerontology (2019) 20:627–647 https://doi.org/10.1007/s10522-019-09818-1 (0123456789().,-volV)( 0123456789().,-volV) RESEARCH ARTICLE Epigenome-wide exploratory study of monozygotic twins suggests differentially methylated regions to associate with hand grip strength Mette Soerensen . Weilong Li . Birgit Debrabant . Marianne Nygaard . Jonas Mengel-From . Morten Frost . Kaare Christensen . Lene Christiansen . Qihua Tan Received: 15 April 2019 / Accepted: 24 June 2019 / Published online: 28 June 2019 Ó The Author(s) 2019 Abstract Hand grip strength is a measure of mus- significant CpG sites or pathways were found, how- cular strength and is used to study age-related loss of ever two of the suggestive top CpG sites were mapped physical capacity. In order to explore the biological to the COL6A1 and CACNA1B genes, known to be mechanisms that influence hand grip strength varia- related to muscular dysfunction. By investigating tion, an epigenome-wide association study (EWAS) of genomic regions using the comb-p algorithm, several hand grip strength in 672 middle-aged and elderly differentially methylated regions in regulatory monozygotic twins (age 55–90 years) was performed, domains were identified as significantly associated to using both individual and twin pair level analyses, the hand grip strength, and pathway analyses of these latter controlling the influence of genetic variation. regions revealed significant pathways related to the Moreover, as measurements of hand grip strength immune system, autoimmune disorders, including performed over 8 years were available in the elderly diabetes type 1 and viral myocarditis, as well as twins (age 73–90 at intake), a longitudinal EWAS was negative regulation of cell differentiation. The genes conducted for this subsample. No genome-wide contributing to the immunological pathways were HLA-B, HLA-C, HLA-DMA, HLA-DPB1, MYH10, ERAP1 and IRF8, while the genes implicated in the negative regulation of cell differentiation were IRF8, Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10522-019-09818-1) con- CEBPD, ID2 and BRCA1. In conclusion, this tains supplementary material, which is available to authorized users. M. Soerensen (&) Á W. Li Á B. Debrabant Á M. Soerensen Á M. Nygaard Á J. Mengel-From Á M. Nygaard Á J. Mengel-From Á K. Christensen Á K. Christensen Á Q. Tan L. Christiansen Á Q. Tan Department of Clinical Genetics, Odense University Epidemiology, Biostatistics and Biodemography, Hospital, J.B. Winsløws Vej 4, 5000 Odense C, Denmark Department of Public Health, University of Southern Denmark, J.B. Winsløws Vej 9B, 5000 Odense C, M. Frost Denmark Endocrine Research Unit, KMEB, University of Southern e-mail: [email protected] Denmark, J.B. Winsløws Vej 4, 5000 Odense C, Denmark M. Soerensen L. Christiansen Department of Clinical Biochemistry and Pharmacology, Department of Clinical Immunology, Copenhagen Center for Individualized Medicine in Arterial Diseases, University Hospital, Rigshospitalet, Blegdamsvej 9, Odense University Hospital, J.B. Winsløws Vej 4, 2100 Copenhagen Ø, Denmark 5000 Odense C, Denmark 123 628 Biogerontology (2019) 20:627–647 exploratory study suggests hand grip strength to Wang et al. 2005; Bohannon et al. 2012). In associate with differentially methylated regions accordance, the average hand grip strength peaks in enriched in immunological and cell differentiation early adulthood, followed by a period of continuance, pathways, and hence merits further investigations. and then starts declining from midlife and throughout life (Frederiksen et al. 2006; Dodds et al. 2014). Hand Keywords Epigenome-wide association study Á grip strength has been associated with a number of Hand grip strength Á Twin data Á Longitudinal data Á adverse health outcomes, such as depression (van Pathway analyses Á Comb-p Milligen et al. 2011; Fukumori et al. 2015), cardio- metabolic risk markers and diseases (Mainous et al. 2015; Lawman et al. 2016; Lee et al. 2016), and multi- Abbreviations morbidity (Cheung et al. 2013; Yorke et al. 2015), as EWAS Epigenome-wide association study well as with an increased overall mortality risk GWAS Genome-wide association study (Newman et al. 2006; Arvandi et al. 2016). In a study TWAS Transcriptome-wide association study of almost 140,000 individuals from 17 different MADT The Study of Middle Aged Danish countries, Leong et al. (2015) found associations Twins between hand grip strength and incident cardiovascu- LSADT The Longitudinal Study of Aging lar disease and further confirmed that hand grip Danish Twins strength is a strong predictor of all-cause and in BWD The Study of Birth Weight Discordant particular cardiovascular mortality. Recently, a study Twins of 502,293 participants from the UK Biobank confirms PCA Principle component analysis an association to all cause mortality and cause specific DMRs Differentially methylated regions mortality from cardiovascular disease, yet also puts FDR False discovery rate forward associations to cause specific mortality from TSS Transcription start site respiratory disease, chronic obstructive pulmonary KEGG The Kyoto Encyclopedia of Genes and disease and cancers, as well as to incidences of Genomes database cardiovascular disease, respiratory diseases, chronic WebGestalt The WEB-based GEne SeT AnaLysis obstructive pulmonary disease and cancers (Celis- Toolkit Morales et al. 2018). In addition, recent literature MSigDB Molecular Signatures Database reviews firmly validate the associations between hand GREAT Genomic regions enrichment grip strength and cognitive decline (Fritz et al. 2017; annotation tool Rijk et al. 2016) and functional status such as activity ORA Overrepresentation enrichment of daily living (Rijk et al. 2016). analysis Previous studies have estimated that the heritability GREA Genomic regions enrichment analysis of hand grip strength is approximately 50–60% (Frederiksen et al. 2002). However, very few consis- tent genetic associations have been found, and large Introduction genome-wide association studies (GWAS) of hand grip strength are scarce compared to other traits, thus Aging is accompanied by a general loss of physical leaving the molecular background of hand grip capacity that is often associated with adverse age- strength largely unaccounted for (Garatachea and related outcomes and thus may have significant Lucı´a 2013; Chan et al. 2015). The very first hand grip influences on the quality of life. For example, age- strength GWAS included 2088 adults (aged related decline in skeletal muscle strength, which is an 55–85 years) and revealed no genome-wide signifi- important component of sarcopenia and frailty, is cant results (Chan et al. 2015). Later, a meta-analysis associated with physical disability, morbidity and of 27,581 individuals over 65 years of age from 14 mortality (Beaudart et al. 2017). different cohorts discovered one genome-wide signif- Hand grip strength is a simple and easily admin- icant association, rs752045, in an intergenic region on istered measurement of muscle strength that correlates chromosome 8, which was replicated in 6363 individ- well with overall muscle strength (Visser et al. 2000; uals from three additional cohorts (Matteini et al. 123 Biogerontology (2019) 20:627–647 629 2016). rs752045 is located in a DNase hypersensitivity associated differentially methylated genomic regions, site known to affect a binding motif of the CCAAT/ of which some showed replication in 1196 individuals: enhancer-binding protein-b (CEBPB), which has been these included the DNAH12, ZFP64, TP63 and implicated in muscle cell differentiation and muscle GUSBP11 genes, which have previously been linked repair (Matteini et al. 2016). Recently, an even larger to muscle differentiation and function (Livshits et al. multi-center GWAS of 195,180 individuals identified 2016). Hence, the latter study suggests the importance 16 loci including genes involved in processes such as of epigenetic approaches for understanding the molec- structure and function of skeletal muscle fibers ular basis of muscle phenotypes such as hand grip (ACTG1), neuronal maintenance and signal transduc- strength, and furthermore supports the use of blood as tion (PEX14, TGFA, SYT1), and monogenic syn- an informative tissue in studies of muscle function. dromes with involvement of psychomotor impairment With the aim of exploring the association between (PEX14, LRPPRC and KANSL1) (Willems et al. hand grip strength and DNA methylation profiles in 2017). blood cells, we studied a sample of 672 monozygotic In addition to genetic studies, blood-based studies twins with an age span of 55–90 years. The study took of molecular signatures may prove valuable for advantage of the twin data by applying an intra-pair determining systemic factors and pathways involved approach, controlling the influence of genetic varia- in muscle strength maintenance and age-related tion and lowering the influence of potential con- decline. A gene expression analysis of blood messen- founders such as differences in rearing environment. ger RNA from 698 people found the expression of the Furthermore, we performed a longitudinal EWAS in CEBPB gene to be significantly associated with hand 192 elderly individuals (age 73–90 years at intake), grip strength as well as with physical performance for whom data on hand grip strength were available (Harries et al. 2012). In a larger transcriptome-wide from up to five survey waves conducted over 8 years. association study (TWAS), Pilling et al. (2016) investigated
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