Transcriptomic and Metabolomic Analyses in Monozygotic and Dizygotic Twins

Nikki Hubers; Gabin Drouard; Rick Jansen; René Pool; Jouke Jan Hottenga; Miina Ollikainen; Xiaoling Wang; Gonneke Willemsen; Jaakko Kaprio; Dorret I. Boomsma; Jenny van Dongen

doi:10.1002/ajmg.a.63971

Transcriptomic and Metabolomic Analyses in Monozygotic and Dizygotic Twins

Nikki Hubers^*
, Gabin Drouard
, Rick Jansen
, René Pool
, Jouke Jan Hottenga
, Miina Ollikainen
, Xiaoling Wang
, Gonneke Willemsen
, Jaakko Kaprio
, Dorret I. Boomsma
, Jenny van Dongen

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Monozygotic (MZ) and dizygotic (DZ) twins are studied to understand genetic and environmental influences on complex traits, however the mechanisms behind twinning are not completely understood. (Epi)genomic studies identified SNPs associated with DZ twinning and DNA methylation sites with MZ twinning. To find molecular biomarkers of twinning, we compared transcriptomics and metabolomics data from MZ and DZ twins. We analyzed 42,663 RNA transcripts in 1453 MZ twins and 1294 DZ twins from the Netherlands Twin Register (NTR), followed by sex-stratified analyses. The top 5% transcripts with lowest p-values were analyzed for replication in 217 MZ and 158 DZ twins from the older Finnish Twin cohort (FTC). In the NTR, one transcript (PURG) was significantly differentially expressed between MZ and DZ twins; but this did not replicate in FTC. Pathway analyses highlighted the WNT-pathway, previously associated with MZ twinning, and the TGF-B and SMAD pathway, previously associated with DZ twinning. Meta-analysis of 169 serum metabolites in 2797 MZ and 2040 DZ twins from the NTR, FTC and FinnTwin12, showed no metabolomic differences. Overall, we did not find replicable transcript-level expression differences in blood between MZ and DZ twins, but highlighted the TGF-B/SMAD pathway as a potential transcriptional biomarker for DZ twinning.

Original language	English
Article number	e63971
Pages (from-to)	1-12
Number of pages	12
Journal	American Journal of Medical Genetics, Part A
Volume	197
Issue number	4
Early online date	16 Dec 2024
DOIs	https://doi.org/10.1002/ajmg.a.63971
Publication status	Published - Apr 2025

Bibliographical note

Publisher Copyright:
© 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.

Funding

NH is supported by the Royal Netherlands Academy of Science Professor Award (PAH/6635). To DIB and the 2023 talent travel grand award by the faculty of behavior and movement sciences at the Vrije Universiteit Amsterdam. JvD is supported by NWO Large Scale infrastructures, X-omics (184.034.019). The NTR is supported by multiple grants from the Netherlands Organizations for Scientific Research (NOW; 480–15-001/674; 480–04-004; 400–05-717); and Medical Research (ZonMW; 912–10-020); the European Science Council (ERC) Genetics of Mental Illness (ERC Advanced, 230374); Developmental trajectories of psychopathology (NIMH 1RC2 MH089995). The metabolomics data of the NTR were collected through BBMRI: BBMRI.1 (184.021.007) and BBMRI.2 (184.033.111). The FTC has been supported by the Academy of Finland (Grants 265240, 263278, 308248, 312073, 336832 to Jaakko Kaprio and 297908 to Miina Ollikainen) and the Sigrid Juselius Foundation (to Miina Ollikainen). The transcriptome study in FTC was supported by NIH/NHLBI grant HL104125. Phenotype and genotype data collection in FinnTwin12 cohort has been supported by, ENGAGE—European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007, grant agreement number 201413, National Institute of Alcohol Abuse and Alcoholism (grants AA-12502, AA-00145, and AA-09203 to R J Rose; AA15416 and K02AA018755 to D M Dick; R01AA015416 to Jessica Salvatore) and the Academy of Finland (grants 100,499, 205,585, 118,555, 141,054, 264,146, 308,248 to JK), and the Center of Excellence in Complex Disease Genetics (grants 312,073, 336,823, and 352,792 to JKaprio). This work largely builds upon the biobanking efforts performed by the BIOS and the BBMRI consortia and we thank all participants and staff for their contributions. Additionally we thank Dr. Fiona Hagenbeek for providing expertise and feedback throughout the project.

Funders	Funder number
FP7-HEALTH-F4-2007
European Science Council
National Institutes of Health
Bermuda Institute of Ocean Sciences
Medical Research
Sigrid Juséliuksen Säätiö
Royal Netherlands Academy of Science	PAH/6635
Genetics of Mental Illness	230374
Center of Excellence in Complex Disease Genetics	352,792, 336,823
Research Council of Finland	312,073, 263278, 265240, 336832, 297908
ZonMw	912–10‐020
National Heart, Lung, and Blood Institute	FP7‐HEALTH‐F4‐2007, HL104125, 201413
National Institute on Alcohol Abuse and Alcoholism	205,585, 141,054, K02AA018755, 118,555, 264,146, AA‐12502, 100,499, AA‐09203, 308248, AA15416, AA‐00145
National Institute of Mental Health	1RC2 MH089995, 184.033.111, 184.021.007
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	184.034.019, 480–15‐001/674, 480–04‐004, 400–05‐717

Keywords

Metabolomics
multi-omics
Transcriptomics
twinning
twins

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Cite this

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title = "Transcriptomic and Metabolomic Analyses in Monozygotic and Dizygotic Twins",

abstract = "Monozygotic (MZ) and dizygotic (DZ) twins are studied to understand genetic and environmental influences on complex traits, however the mechanisms behind twinning are not completely understood. (Epi)genomic studies identified SNPs associated with DZ twinning and DNA methylation sites with MZ twinning. To find molecular biomarkers of twinning, we compared transcriptomics and metabolomics data from MZ and DZ twins. We analyzed 42,663 RNA transcripts in 1453 MZ twins and 1294 DZ twins from the Netherlands Twin Register (NTR), followed by sex-stratified analyses. The top 5\% transcripts with lowest p-values were analyzed for replication in 217 MZ and 158 DZ twins from the older Finnish Twin cohort (FTC). In the NTR, one transcript (PURG) was significantly differentially expressed between MZ and DZ twins; but this did not replicate in FTC. Pathway analyses highlighted the WNT-pathway, previously associated with MZ twinning, and the TGF-B and SMAD pathway, previously associated with DZ twinning. Meta-analysis of 169 serum metabolites in 2797 MZ and 2040 DZ twins from the NTR, FTC and FinnTwin12, showed no metabolomic differences. Overall, we did not find replicable transcript-level expression differences in blood between MZ and DZ twins, but highlighted the TGF-B/SMAD pathway as a potential transcriptional biomarker for DZ twinning.",

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AU - Hubers, Nikki

AU - Drouard, Gabin

AU - Jansen, Rick

AU - Pool, René

AU - Hottenga, Jouke Jan

AU - Ollikainen, Miina

AU - Wang, Xiaoling

AU - Willemsen, Gonneke

AU - Kaprio, Jaakko

AU - Boomsma, Dorret I.

AU - van Dongen, Jenny

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AB - Monozygotic (MZ) and dizygotic (DZ) twins are studied to understand genetic and environmental influences on complex traits, however the mechanisms behind twinning are not completely understood. (Epi)genomic studies identified SNPs associated with DZ twinning and DNA methylation sites with MZ twinning. To find molecular biomarkers of twinning, we compared transcriptomics and metabolomics data from MZ and DZ twins. We analyzed 42,663 RNA transcripts in 1453 MZ twins and 1294 DZ twins from the Netherlands Twin Register (NTR), followed by sex-stratified analyses. The top 5% transcripts with lowest p-values were analyzed for replication in 217 MZ and 158 DZ twins from the older Finnish Twin cohort (FTC). In the NTR, one transcript (PURG) was significantly differentially expressed between MZ and DZ twins; but this did not replicate in FTC. Pathway analyses highlighted the WNT-pathway, previously associated with MZ twinning, and the TGF-B and SMAD pathway, previously associated with DZ twinning. Meta-analysis of 169 serum metabolites in 2797 MZ and 2040 DZ twins from the NTR, FTC and FinnTwin12, showed no metabolomic differences. Overall, we did not find replicable transcript-level expression differences in blood between MZ and DZ twins, but highlighted the TGF-B/SMAD pathway as a potential transcriptional biomarker for DZ twinning.

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ER -

Transcriptomic and Metabolomic Analyses in Monozygotic and Dizygotic Twins

Abstract

Bibliographical note

Funding

Keywords

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