Publications by authors named "Marika A Kaakinen"

9 Publications

  • Page 1 of 1

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Risk of Recurrent Pregnancy Loss in the Ukrainian Population Using a Combined Effect of Genetic Variants: A Case-Control Study.

Genes (Basel) 2021 01 5;12(1). Epub 2021 Jan 5.

Institute of Molecular Biology and Genetics NAS, 03143 Kiev, Ukraine.

We assessed the predictive ability of a combined genetic variant panel for the risk of recurrent pregnancy loss (RPL) through a case-control study. Our study sample was from Ukraine and included 114 cases with idiopathic RPL and 106 controls without any pregnancy losses/complications and with at least one healthy child. We genotyped variants within 12 genetic loci reflecting the main biological pathways involved in pregnancy maintenance: blood coagulation (, , , ), hormonal regulation (, ), endometrium and placental function (, ), folate metabolism () and inflammatory response (, , ). We showed that a genetic risk score (GRS) calculated from the 12 variants was associated with an increased risk of RPL (odds ratio 1.56, 95% CI: 1.21, 2.04, 8.7 × 10). The receiver operator characteristic (ROC) analysis resulted in an area under the curve (AUC) of 0.64 (95% CI: 0.57, 0.72), indicating an improved ability of the GRS to classify women with and without RPL. Ιmplementation of the GRS approach can help define women at higher risk of complex multifactorial conditions such as RPL. Future well-powered genome-wide association studies will help in dissecting biological pathways previously unknown for RPL and further improve the identification of women with RPL susceptibility.
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http://dx.doi.org/10.3390/genes12010064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824779PMC
January 2021

Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.

Nat Commun 2021 01 5;12(1):24. Epub 2021 Jan 5.

Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA.

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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http://dx.doi.org/10.1038/s41467-020-19366-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785747PMC
January 2021

Alzheimer's disease pathology explains association between dementia with Lewy bodies and APOE-ε4/TOMM40 long poly-T repeat allele variants.

Alzheimers Dement (N Y) 2019 20;5:814-824. Epub 2019 Nov 20.

Neuroepidemiology and Ageing Research Unit, School of Public Health, Imperial College London, London, UK.

Introduction: The role of 19q13.3 region variants is well documented in Alzheimer's disease (AD) but remains contentious in dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD).

Methods: We dissected genetic profiles within the region in 451 individuals from four European brain banks, including DLB and PDD cases with/without neuropathological evidence of AD-related pathology and healthy controls.

Results: -L/-ε4 alleles were associated with DLB (OR  = 3.61; value = 3.23 × 10; OR  = 3.75; value = 4.90 × 10) and earlier age at onset of DLB (HR  = 1.33, value = .031; HR  = 1.46, value = .004), but not with PDD. The -L/-ε4 effect was most pronounced in DLB individuals with concomitant AD pathology (OR  = 4.40, value = 1.15 × 10; OR  = 5.65, value = 2.97 × 10) but was not significant in DLB without AD. Meta-analyses combining all -ε4 data in DLB confirmed our findings (OR = 2.93, value = 3.78 × 10; OR = 5.36, value = 1.56 × 10).

Discussion: -ε4/ -L alleles increase susceptibility and risk of earlier DLB onset, an effect explained by concomitant AD-related pathology. These findings have important implications in future drug discovery and development efforts in DLB.
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http://dx.doi.org/10.1016/j.trci.2019.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880091PMC
November 2019

Genome-wide association study identifies 74 loci associated with educational attainment.

Nature 2016 05 11;533(7604):539-42. Epub 2016 May 11.

Department of Neurology, General Hospital and Medical University Graz, Graz 8036, Austria.

Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.
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http://dx.doi.org/10.1038/nature17671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4883595PMC
May 2016

Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses.

Nat Genet 2016 06 18;48(6):624-33. Epub 2016 Apr 18.

Max Planck Institute for Human Development, Berlin, Germany.

Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ^| ≈ 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.
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http://dx.doi.org/10.1038/ng.3552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4884152PMC
June 2016
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