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Data Management Plan: Genomic Underpinnings Of Sex Differences In Health And Disease [article]

Taru Tukiainen
2018 Zenodo  
Data Management Plan for Academy of Finland 2017: Genomic underpinnings of sex differences in health and disease
doi:10.5281/zenodo.1303844 fatcat:j6g3yx3urfbrhlwmxec7rz6cxe

Transient modification of lin28b expression - Permanent effects on zebrafish growth

Jaakko T. Leinonen, Yu-Chia Chen, Taru Tukiainen, Pertti Panula, Elisabeth Widén
2018 Molecular and Cellular Endocrinology  
Recent genome-wide association studies and mouse models have identified LIN28B as a gene affecting several pubertal timing-related traits and vertebrate growth. However, the exact biological mechanisms underlying the associations remain unknown. We have explored the mechanisms linking LIN28B with growth regulation by combining human gene expression data with functional models. Specifically, we show that 1) pubertal timingassociated genetic variation correlates with LIN28B expression in the
more » ... tary and hypothalamus, 2) downregulating lin28b in zebrafish embryos associates with aberrant development of kiss2-neurons, and 3) increasing lin28b expression transiently by synthetic mRNA injections during embryogenesis results in sustained enhancement of zebrafish growth. Unexpectedly, the mRNA injections resulted in advanced sexual maturation of female fish, suggesting that lin28b may influence pubertal timing through multiple developmental mechanisms. Overall, these results provide novel insight into LIN28B function in vertebrate growth regulation, emphasizing the importance of the gene and related genetic pathways for embryonic and juvenile development.
doi:10.1016/j.mce.2018.09.001 pmid:30196135 fatcat:gv3e3ajbhvgopnkzvgyvzftvke

Lipidome- and genome-wide study to understand sex differences in circulatory lipids [article]

Rubina Tabassum, Sanni Ruotsalainen, Linda Ottensmann, Mathias J. Gerl, Christian Klose, Taru Tukiainen, Matti Pirinen, Kai Simons, Elisabeth Widén, Samuli Ripatti
2022 medRxiv   pre-print
AbstractDespite well-recognized difference in the atherosclerotic cardiovascular disease (ASCVD) risk between men and women, sex differences in risk factors and sex specific mechanisms in the pathophysiology of ASCVD remain poorly understood. Lipid metabolism plays a central role in the development of ASCVD. Understanding sex differences in lipids and their genetic determinants could provide mechanistic insights into sex differences in ASCVD and aid in precise risk assessment. Thus, we examined
more » ... sex differences in plasma levels of 179 lipid species from 7,266 participants and performed sex-stratified genome-wide association studies (GWAS) to evaluate contribution of genetic factors in sex differences. We sought for replication using independent data from 2,045 participants. Significant sex differences in levels of 141 lipid species were observed (P<7.0×10−4). Interestingly, 121 lipid species showed significant age-sex interactions with opposite age-related changes in 39 lipid species. In general, most of the cholesteryl esters, ceramides, lysophospholipids and glycerides were higher in 45-50-year-old men compared with women of same age, but the sex-differences narrowed down or reversed with age. We did not observe any major differences in genetic effect in the sex stratified GWAS which suggests that common genetic variants do not have a major role in sex differences in lipidome. In conclusion, our study provides a comprehensive view of sex differences in circulatory lipids pointing to potential sex differences in lipid metabolism, highlighting need for sex- and age-specific prevention strategies.
doi:10.1101/2022.05.30.22275704 fatcat:3zy2srmaobe7nf67tvowoqrrjy

Mergeomics: integration of diverse genomics resources to identify pathogenic perturbations to biological systems [article]

Le Shu, Yuqi Zhao, Zeyneb Kurt, Sean Geoffrey Byars, Taru Tukiainen, Johannes Kettunen, Samuli Ripatti, Bin Zhang, Michael Inouye, Ville-Petteri Makinen, Xia Yang
2016 bioRxiv   pre-print
Mergeomics is a computational pipeline (http://mergeomics.research.idre.ucla.edu/Download/Package/) that integrates multidimensional omics-disease associations, functional genomics, canonical pathways and gene-gene interaction networks to generate mechanistic hypotheses. It first identifies biological pathways and tissue-specific gene subnetworks that are perturbed by disease-associated molecular entities. The disease-associated subnetworks are then projected onto tissue-specific gene-gene
more » ... action networks to identify local hubs as potential key drivers of pathological perturbations. The pipeline is modular and can be applied across species and platform boundaries, and uniquely conducts pathway/network level meta-analysis of multiple genomic studies of various data types. Application of Mergeomics to cholesterol datasets revealed novel regulators of cholesterol metabolism.
doi:10.1101/036012 fatcat:bxrsjhexlrh6blt4wfz3w5rkwa

High-resolution population-specific recombination rates and their effect on phasing and genotype imputation [article]

Shabbeer Hassan, Ida Surakka, Marja-Riita Taskinen, Veikko Salomaa, Aarno Palotie, Maija Wessman, Taru Tukiainen, Matti Pirinen, Priit Palta, Samuli Ripatti
2020 bioRxiv   pre-print
Recombination is an essential part of meiosis as it facilitates novel combinations of homologous chromosomes, following their successive segregation in offspring. Founder population size, demographic changes (eg. population bottlenecks or rapid expansion) can lead to variation in recombination rates across different populations. Previous research has shown that using population-specific reference panels has a significant effect on downstream population genomic analysis like haplotype phasing,
more » ... notype imputation and association, especially in the context of population isolates. Here, we developed a high-resolution recombination rate mapping at 10kb and 50kb scale using high-coverage (20-30x) whole-genome sequencing (WGS) data of 55 family trios from Finland and compared it to recombination rates of non-Finnish Europeans (NFE). We then tested the downstream effects of the population-specific recombination rates in statistical phasing and genotype imputation in Finns as compared to the same analyses performed by using the NFE-based recombination rates. Finnish recombination rates have a moderately high correlation (Spearman rho =0.67-0.79) with non-Finnish Europeans, although on average (across all autosomal chromosomes), Finnish rates (2.268±0.4209 cM/Mb) are 12-14% lower than NFE (2.641±0.5032 cM/Mb). Population-specific effective population sizes were found to have no significant effect in haplotype phasing accuracy (switch error rates, SER″2%) and average imputation concordance rates (with reference panels in phasing: rates were 97-98% for common, 92-96% for low frequency and 78-90% for rare variants) irrespective of the recombination map used. Similarly, we found no effect of population-specific (Finnish) recombination maps in phasing with comparable switch error rates (SER) across autosomes when compared to HapMap based maps. Our results suggest that downstream population genomic analyses like haplotype phasing and genotype imputation mostly depend on population-specific contexts like appropriate reference panels and their sample size, but not on population-specific recombination maps or effective population sizes. Currently, available HapMap recombination maps seem robust for population-specific phasing and imputation pipelines, even in the context of relatively isolated populations like Finland.
doi:10.1101/2020.05.20.106831 fatcat:4mymht25ijem7eec7unzyay2kq

LIN28B affects gene expression at the hypothalamic-pituitary axis and serum testosterone levels

Jaakko T Leinonen, Yu-Chia Chen, Jana Pennonen, Leevi Lehtonen, Nella Junna, Taru Tukiainen, Pertti Panula, Elisabeth Widén
2019 Scientific Reports  
Genome-wide association studies (GWAS) have recurrently associated sequence variation nearby LIN28B with pubertal timing, growth and disease. However, the biology linking LIN28B with these traits is still poorly understood. With our study, we sought to elucidate the mechanisms behind the LIN28B associations, with a special focus on studying LIN28B function at the hypothalamic-pituitary (HP) axis that is ultimately responsible for pubertal onset. Using CRISPR-Cas9 technology, we first generated
more » ... in28b knockout (KO) zebrafish. Compared to controls, the lin28b KO fish showed both accelerated growth tempo, reduced adult size and increased expression of mitochondrial genes during larval development. Importantly, data from the knockout zebrafish models and adult humans imply that LIN28B expression has potential to affect gene expression in the HP axis. Specifically, our results suggest that LIN28B expression correlates positively with the expression of ESR1 in the hypothalamus and POMC in the pituitary. Moreover, we show how the pubertal timing advancing allele (T) for rs7759938 at the LIN28B locus associates with higher testosterone levels in the UK Biobank data. Overall, we provide novel evidence that LIN28B contributes to the regulation of sex hormone pathways, which might help explain why the gene associates with several distinct traits.
doi:10.1038/s41598-019-54475-6 pmid:31792362 pmcid:PMC6889388 fatcat:fc2a7zojhzcflneyuezdhu6gju

Integration of biomarker polygenic risk score improves prediction of coronary heart disease in UK Biobank and FinnGen [article]

Jake Lin, Nina Mars, Yu Fu, Pietari Ripatti, Tuomo Kiiskinen, Taru Tukiainen, Samuli Ripatti, Matti Pirinen, FinnGen
2022 medRxiv   pre-print
In addition to age and sex, also smoking history and levels of blood pressure, cholesterol, lipoproteins and inflammation are established biomarkers for coronary heart disease (CHD). As standard polygenic risk scores (PRS) have recently proven successful for CHD prediction, it remains of high interest to determine how a combined PRS of biomarkers (BioPRS) constructed from statistically relevant biomarkers can further improve genetic prediction of CHD. Methods We developed CHDBioPRS, which
more » ... es BioPRS with PRS of CHD, via regularized regression in UK Biobank (UKB) training data (n = 208,010). The resulting CHDBioPRS was tested on an independent UK Biobank subset (n = 25,765) and on the FinnGen study (n = 306,287). Results We observed a consistent pattern across all data sets where BioPRS was clearly predictive of CHD and improved standard PRS for CHD when the two were combined. In UKB test data, CHDPRS had a hazard ratio (HR) of 1.78 (95% confidence interval 1.67-1.91, area under the curve (AUC) 0.808) and CHDBioPRS had a HR of 1.88 (1.75-2.01, AUC 0.811) per one standard deviation of PRS. In FinnGen data, HR of CHDPRS was 1.57 (1.55-1.60, AUC 0.752) and HR of CHDBioPRS was 1.60 (1.58-1.62, AUC 0.755). We observed larger effects of CHDBioPRS in subsets of early onset cases with HR of 2.07 (1.85-2.32, AUC 0.790) in UKB test data and of 2.10 (2.04-2.16, AUC 0.791) in FinnGen. Results were similar when stratified by sex. Conclusions Integration of biomarker based BioPRS improved on the standard PRS for CHD and the gain was largest with early onset CHD cases. These findings highlight the benefit of enriching polygenic risk prediction of CHD with the genetics of associated biomarkers.
doi:10.1101/2022.08.22.22279057 fatcat:lhojyw3oazesldgdsnulzsaimq

Mergeomics: multidimensional data integration to identify pathogenic perturbations to biological systems

Le Shu, Yuqi Zhao, Zeyneb Kurt, Sean Geoffrey Byars, Taru Tukiainen, Johannes Kettunen, Luz D. Orozco, Matteo Pellegrini, Aldons J. Lusis, Samuli Ripatti, Bin Zhang, Michael Inouye (+2 others)
2016 BMC Genomics  
Complex diseases are characterized by multiple subtle perturbations to biological processes. New omics platforms can detect these perturbations, but translating the diverse molecular and statistical information into testable mechanistic hypotheses is challenging. Therefore, we set out to create a public tool that integrates these data across multiple datasets, platforms, study designs and species in order to detect the most promising targets for further mechanistic studies. Results: We
more » ... Mergeomics, a computational pipeline consisting of independent modules that 1) leverage multi-omics association data to identify biological processes that are perturbed in disease, and 2) overlay the diseaseassociated processes onto molecular interaction networks to pinpoint hubs as potential key regulators. Unlike existing tools that are mostly dedicated to specific data type or settings, the Mergeomics pipeline accepts and integrates datasets across platforms, data types and species. We optimized and evaluated the performance of Mergeomics using simulation and multiple independent datasets, and benchmarked the results against alternative methods. We also demonstrate the versatility of Mergeomics in two case studies that include genome-wide, epigenome-wide and transcriptome-wide datasets from human and mouse studies of total cholesterol and fasting glucose. In both cases, the Mergeomics pipeline provided statistical and contextual evidence to prioritize further investigations in the wet lab. The software implementation of Mergeomics is freely available as a Bioconductor R package. Conclusion: Mergeomics is a flexible and robust computational pipeline for multidimensional data integration. It outperforms existing tools, and is easily applicable to datasets from different studies, species and omics data types for the study of complex traits.
doi:10.1186/s12864-016-3198-9 pmid:27814671 pmcid:PMC5097440 fatcat:lf7obgyrg5ed3fjisdrkjf36fi

A Differential Network Approach to Exploring Differences between Biological States: An Application to Prediabetes

Beatriz Valcárcel, Peter Würtz, Nafisa-Katrin Seich al Basatena, Taru Tukiainen, Antti J. Kangas, Pasi Soininen, Marjo-Riitta Järvelin, Mika Ala-Korpela, Timothy M. Ebbels, Maria de Iorio, Peter Csermely
2011 PLoS ONE  
Variations in the pattern of molecular associations are observed during disease development. The comprehensive analysis of molecular association patterns and their changes in relation to different physiological conditions can yield insight into the biological basis of disease-specific phenotype variation. Methodology: Here, we introduce a formal statistical method for the differential analysis of molecular associations via network representation. We illustrate our approach with extensive data
more » ... lipoprotein subclasses measured by NMR spectroscopy in 4,406 individuals with normal fasting glucose, and 531 subjects with impaired fasting glucose (prediabetes). We estimate the pair-wise association between measures using shrinkage estimates of partial correlations and build the differential network based on this measure of association. We explore the topological properties of the inferred network to gain insight into important metabolic differences between individuals with normal fasting glucose and prediabetes. Conclusions/Significance: Differential networks provide new insights characterizing differences in biological states. Based on conventional statistical methods, few differences in concentration levels of lipoprotein subclasses were found between individuals with normal fasting glucose and individuals with prediabetes. By performing the differential analysis of networks, several characteristic changes in lipoprotein metabolism known to be related to diabetic dyslipidemias were identified. The results demonstrate the applicability of the new approach to identify key molecular changes inaccessible to standard approaches.
doi:10.1371/journal.pone.0024702 pmid:21980352 pmcid:PMC3181317 fatcat:5a4s73ymbndr7nkrtr4fdy7usm

High-resolution population-specific recombination rates and their effect on phasing and genotype imputation

Shabbeer Hassan, Ida Surakka, Marja-Riitta Taskinen, Veikko Salomaa, Aarno Palotie, Maija Wessman, Taru Tukiainen, Matti Pirinen, Priit Palta, Samuli Ripatti
2020 European Journal of Human Genetics  
AbstractPrevious research has shown that using population-specific reference panels has a significant effect on downstream population genomic analyses like haplotype phasing, genotype imputation, and association, especially in the context of population isolates. Here, we developed a high-resolution recombination rate mapping at 10 and 50 kb scale using high-coverage (20–30×) whole-genome sequenced data of 55 family trios from Finland and compared it to recombination rates of non-Finnish
more » ... s (NFE). We tested the downstream effects of the population-specific recombination rates in statistical phasing and genotype imputation in Finns as compared to the same analyses performed by using the NFE-based recombination rates. We found that Finnish recombination rates have a moderately high correlation (Spearman's ρ = 0.67–0.79) with NFE, although on average (across all autosomal chromosomes), Finnish rates (2.268 ± 0.4209 cM/Mb) are 12–14% lower than NFE (2.641 ± 0.5032 cM/Mb). Finnish recombination map was found to have no significant effect in haplotype phasing accuracy (switch error rates ~2%) and average imputation concordance rates (97–98% for common, 92–96% for low frequency and 78–90% for rare variants). Our results suggest that haplotype phasing and genotype imputation mostly depend on population-specific contexts like appropriate reference panels and their sample size, but not on population-specific recombination maps. Even though recombination rate estimates had some differences between the Finnish and NFE populations, haplotyping and imputation had not been noticeably affected by the recombination map used. Therefore, the currently available HapMap recombination maps seem robust for population-specific phasing and imputation pipelines, even in the context of relatively isolated populations like Finland.
doi:10.1038/s41431-020-00768-8 pmid:33249422 pmcid:PMC8114909 fatcat:wxnqbr4bdvf6zpaxyv57whqktm

Landscape of X chromosome inactivation across human tissues [article]

Taru Tukiainen, Alexandra-Chloé Villani, Angela Yen, Manuel A. Rivas, Jamie L. Marshall, Rahul Satija, Matt Aguirre, Laura Gauthier, Mark Fleharty, Andrew Kirby, Beryl B. Cummings, Stephane E. Castel (+8 others)
2016 bioRxiv   pre-print
PLoS Genet 4, e9, doi:10.1371/journal.pgen.0040009 (2008). 6 Tukiainen, T. et al.  ... 
doi:10.1101/073957 fatcat:qjkfoeuwhjgvhcxnkwjjxru2ri

Genetic analyses on the health impacts of testosterone highlight effects on female-specific diseases and sex differences [article]

Jaakko T Leinonen, Nina Mars, Leevi E Lehtonen, Ari Ahola-Olli, Sanni E Ruotsalainen, Terho Lehtimaki, Mika Kahonen, Olli Raitakari, Mark J Daly, Tiinamaija Tuomi, Samuli Ripatti, Matti Pirinen (+1 others)
2021 medRxiv   pre-print
Testosterone (T) is linked with diverse characteristics of human health, yet, whether these associations reflect correlation or causation remains debated. Here, we provide a broad perspective on the role of T on complex diseases in both sexes leveraging genetic and health registry data from the UK Biobank and FinnGen (total N=625,650). We find genetically predicted T affects sex-biased and sex-specific traits, with a particularly pronounced impact on female reproductive health. We show T levels
more » ... are intricately involved in metabolism, sharing many associations with sex hormone binding globulin (SHBG), but report lack of direct causality behind most of these associations. Across other disease domains, including behavior, we find little evidence for a significant contribution from normal variation in T levels. Highlighting T's unique biology, we show T displays antagonistic effects on stroke risk and reproduction in males and females. Overall, we underscore the involvement of T in both male and female health, and the complex mechanisms linking T levels to disease risk and sex differences.
doi:10.1101/2021.04.23.21255981 fatcat:orjtb5lnx5f63ltwbyaxqty4gq

Polygenic Hyperlipidemias and Coronary Artery Disease Risk

Pietari Ripatti, Joel T. Rämö, Nina J. Mars, Yu Fu, Jake Lin, Sanni Söderlund, Christian Benner, Ida Surakka, Tuomo Kiiskinen, Aki S. Havulinna, Priit Palta, Nelson B. Freimer (+8 others)
2020 Circulation Genomic and Precision Medicine  
Hyperlipidemia is a highly heritable risk factor for coronary artery disease (CAD). While monogenic familial hypercholesterolemia associates with severely increased CAD risk, it remains less clear to what extent a high polygenic load of a large number of LDL (low-density lipoprotein) cholesterol (LDL-C) or triglyceride (TG)-increasing variants associates with increased CAD risk. Methods: We derived polygenic risk scores (PRSs) with ≈6M variants separately for LDL-C and TG with weights from a UK
more » ... Biobank–based genome-wide association study with ≈324K samples. We evaluated the impact of polygenic hypercholesterolemia and hypertriglyceridemia to lipid levels in 27 039 individuals from the National FINRISK Study (FINRISK) cohort and to CAD risk in 135 638 individuals (13 753 CAD cases) from the FinnGen project (FinnGen). Results: In FINRISK, median LDL-C was 3.39 (95% CI, 3.38–3.40) mmol/L, and it ranged from 2.87 (95% CI, 2.82–2.94) to 3.78 (95% CI, 3.71–3.83) mmol/L between the lowest and highest 5% of the LDL-C PRS distribution. Median TG was 1.19 (95% CI, 1.18–1.20) mmol/L, ranging from 0.97 (95% CI, 0.94–1.00) to 1.55 (95% CI, 1.48–1.61) mmol/L with the TG PRS. In FinnGen, comparing the highest 5% of the PRS to the lowest 95%, CAD odds ratio was 1.36 (95% CI, 1.24–1.49) for the LDL-C PRS and 1.31 (95% CI, 1.19–1.43) for the TG PRS. These estimates were only slightly attenuated when adjusting for a CAD PRS (odds ratio, 1.26 [95% CI, 1.16–1.38] for LDL-C and 1.24 [95% CI, 1.13–1.36] for TG PRS). Conclusions: The CAD risk associated with a high polygenic load for lipid-increasing variants was proportional to their impact on lipid levels and partially overlapping with a CAD PRS. In contrast with a PRS for CAD, the lipid PRSs point to known and directly modifiable risk factors providing additional guidance for clinical translation.
doi:10.1161/circgen.119.002725 fatcat:vz5aztfcrrexxplps5kfyqvdny

Corrigendum: Landscape of X chromosome inactivation across human tissues

Taru Tukiainen, Alexandra-Chloé Villani, Angela Yen, Manuel A. Rivas, Jamie L. Marshall, Rahul Satija, Matt Aguirre, Laura Gauthier, Mark Fleharty, Andrew Kirby, Beryl B. Cummings, Stephane E. Castel (+9 others)
2018 Nature  
doi:10.1038/nature25993 pmid:29517003 fatcat:te7trvnlofdidn4l2fvsv6yqry

Genetic variant in SPDL1 reveals novel mechanism linking pulmonary fibrosis risk and cancer protection [article]

Jukka T. Koskela, Paavo Happola, Aoxing Liu, Juulia Partanen, Giulio Genovese, Mykyta Artomov, Mikko N.M. Myllymaki, Masahiro Kanai, Wei Zhou, Juha Karjalainen, Teemu Palviainen, Justiina Ronkainen (+11 others)
2021 medRxiv   pre-print
Idiopathic Pulmonary Fibrosis (IPF) is a rare disease with poor prognosis. By contrast, cancer is common in any elderly population and a leading killer, but is now often curable. Of note, whereas IPF is driven by cellular senescence, cancer is characterized by uncontrolled cell division. Using data available from two large biobank-based studies (Finnish FinnGen study and UK biobank), we conducted a comprehensive analysis of the shared genetic background of IPF and cancer. In a population sample
more » ... of 218,792 Finns with complete longitudinal health histories, we estimated the effect of individual genetic variants to the lifetime risk of IPF and cancer. We extend the analysis from IPF-GWAS to pan-cancer meta-analysis over FinnGen and UK Biobank and finally to the identification of genetic drivers of somatic chromosomal alterations. We detected six loci (SPDL1, MAD1L1, MAP2K1, RTEL1-STMN3, TERC-ACTRT3, OBFC1) associated with both IPF and cancer, all closely related to cellular division. However, each individual signal is found with opposite effects over the two diseases, termed as antagonistic pleiotropy. Several of these loci (TERC-ACTRT3, RTEL1-STMN3, OBFC1) are among the strongest inherited factors for constitutive telomere length variation and consistently indicate that shorter telomere length would increase the risk for IPF but protect from malignancy. However, a Finnish enriched SPDL1 missense variant and a common MAD1L1 intronic variant had no effect on telomere length but were shown to protect individuals from accumulation of somatic mutations. The decreased risk of cancer in SPDL1 and MAD1L1 variant carriers might result from a lower number of chromosomal alterations accumulated over time, conversely leading to fibrosis in the lung due to cellular senescence-induced inflammation. We hypothesize that the SPDL1 missense variant functions as gain-of-function mutation, leading to cellular senescence, a barrier to cancer and a driver of fibrosis in IPF. If translated to therapy, these findings might not only be able to offer relief to individuals with IPF, but also to protect from onset of cancer.
doi:10.1101/2021.05.07.21255988 fatcat:o4xlhlyw4vgubkfjxafoppbmtq
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