Publications by authors named "Ida Surakka"

94 Publications

Regulatory variants in TCF7L2 are associated with thoracic aortic aneurysm.

Am J Hum Genet 2021 09 14;108(9):1578-1589. Epub 2021 Jul 14.

K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim 7030, Norway.

Thoracic aortic aneurysm (TAA) is characterized by dilation of the aortic root or ascending/descending aorta. TAA is a heritable disease that can be potentially life threatening. While 10%-20% of TAA cases are caused by rare, pathogenic variants in single genes, the origin of the majority of TAA cases remains unknown. A previous study implicated common variants in FBN1 with TAA disease risk. Here, we report a genome-wide scan of 1,351 TAA-affected individuals and 18,295 control individuals from the Cardiovascular Health Improvement Project and Michigan Genomics Initiative at the University of Michigan. We identified a genome-wide significant association with TAA for variants within the third intron of TCF7L2 following replication with meta-analysis of four additional independent cohorts. Common variants in this locus are the strongest known genetic risk factor for type 2 diabetes. Although evidence indicates the presence of different causal variants for TAA and type 2 diabetes at this locus, we observed an opposite direction of effect. The genetic association for TAA colocalizes with an aortic eQTL of TCF7L2, suggesting a functional relationship. These analyses predict an association of higher expression of TCF7L2 with TAA disease risk. In vitro, we show that upregulation of TCF7L2 is associated with BCL2 repression promoting vascular smooth muscle cell apoptosis, a key driver of TAA disease.
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http://dx.doi.org/10.1016/j.ajhg.2021.06.016DOI Listing
September 2021

Genome-wide association study of cardiac troponin I in the general population.

Hum Mol Genet 2021 May 7. Epub 2021 May 7.

Division of Research and Innovation, Akershus University Hospital, 1478 Lørenskog, Norway.

Circulating cardiac troponin proteins are associated with structural heart disease and predict incident cardiovascular disease in the general population. However, the genetic contribution to cardiac troponin I (cTnI) concentrations and its causal effect on cardiovascular phenotypes is unclear. We combine data from two large population-based studies, the Trøndelag Health Study and the Generation Scotland Scottish Family Health Study and perform a genome-wide association study of high-sensitivity cTnI concentrations with 48 115 individuals. We further use two-sample Mendelian randomization to investigate the causal effects of circulating cTnI on acute myocardial infarction (AMI) and heart failure (HF). We identified 12 genetic loci (8 novel) associated with cTnI concentrations. Associated protein-altering variants highlighted putative functional genes: CAND2, HABP2, ANO5, APOH, FHOD3, TNFAIP2, KLKB1 and LMAN1. Phenome-wide association tests in 1688 phecodes and 83 continuous traits in UK Biobank showed associations between a genetic risk score for cTnI and cardiac arrhythmias, metabolic and anthropometric measures. Using two-sample Mendelian randomization we confirmed the non-causal role of cTnI in AMI (5948 cases, 355 246 controls). We found indications for a causal role of cTnI in HF (47 309 cases and 930 014 controls), but this was not supported by secondary analyses using left ventricular mass as outcome (18 257 individuals). Our findings clarify the biology underlying the heritable contribution to circulating cTnI and support cTnI as a non-causal biomarker for AMI and HF development in the general population. Using genetically informed methods for causal inference helps inform the role and value of measuring cTnI in the general population.
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http://dx.doi.org/10.1093/hmg/ddab124DOI Listing
May 2021

ANGPTL8 protein-truncating variant associated with lower serum triglycerides and risk of coronary disease.

PLoS Genet 2021 04 28;17(4):e1009501. Epub 2021 Apr 28.

Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.

Protein-truncating variants (PTVs) affecting dyslipidemia risk may point to therapeutic targets for cardiometabolic disease. Our objective was to identify PTVs that were associated with both lipid levels and the risk of coronary artery disease (CAD) or type 2 diabetes (T2D) and assess their possible associations with risks of other diseases. To achieve this aim, we leveraged the enrichment of PTVs in the Finnish population and tested the association of low-frequency PTVs in 1,209 genes with serum lipid levels in the Finrisk Study (n = 23,435). We then tested which of the lipid-associated PTVs were also associated with the risks of T2D or CAD, as well as 2,683 disease endpoints curated in the FinnGen Study (n = 218,792). Two PTVs were associated with both lipid levels and the risk of CAD or T2D: triglyceride-lowering variants in ANGPTL8 (-24.0[-30.4 to -16.9] mg/dL per rs760351239-T allele, P = 3.4 × 10-9) and ANGPTL4 (-14.4[-18.6 to -9.8] mg/dL per rs746226153-G allele, P = 4.3 × 10-9). The risk of T2D was lower in carriers of the ANGPTL4 PTV (OR = 0.70[0.60-0.81], P = 2.2 × 10-6) than noncarriers. The odds of CAD were 47% lower in carriers of a PTV in ANGPTL8 (OR = 0.53[0.37-0.76], P = 4.5 × 10-4) than noncarriers. Finally, the phenome-wide scan of the ANGPTL8 PTV showed that the ANGPTL8 PTV carriers were less likely to use statin therapy (68,782 cases, OR = 0.52[0.40-0.68], P = 1.7 × 10-6) compared to noncarriers. Our findings provide genetic evidence of potential long-term efficacy and safety of therapeutic targeting of dyslipidemias.
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http://dx.doi.org/10.1371/journal.pgen.1009501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8109807PMC
April 2021

Translating genetic association of lipid levels for biological and clinical application.

Cardiovasc Drugs Ther 2021 06 19;35(3):617-626. Epub 2021 Feb 19.

Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Michigan Medicine, Ann Arbor, MI, USA.

Purpose Of Review: This review focuses on the foundational evidence from the last two decades of lipid genetics research and describes the current status of data-driven approaches for transethnic GWAS, fine-mapping, transcriptome informed fine-mapping, and disease prediction.

Recent Findings: Current lipid genetics research aims to understand the association mechanisms and clinical relevance of lipid loci as well as to capture population specific associations found in global ancestries. Recent genome-wide trans-ethnic association meta-analyses have identified 118 novel lipid loci reaching genome-wide significance. Gene-based burden tests of whole exome sequencing data have identified three genes-PCSK9, LDLR, and APOB-with significant rare variant burden associated with familial dyslipidemia. Transcriptome-wide association studies discovered five previously unreported lipid-associated loci. Additionally, the predictive power of genome-wide genetic risk scores amalgamating the polygenic determinants of lipid levels can potentially be used to increase the accuracy of coronary artery disease prediction.

Conclusions: Lipids are one of the most successful group of traits in the era of genome-wide genetic discovery for identification of novel loci and plausible drug targets. However, a substantial fraction of lipid trait heritability remains unexplained. Further analysis of diverse ancestries and state of the art methods for association locus refinement could potentially reveal some of this missing heritability and increase the clinical application of the genomic association results.
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http://dx.doi.org/10.1007/s10557-021-07156-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8272953PMC
June 2021

Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease.

Nat Commun 2020 12 18;11(1):6417. Epub 2020 Dec 18.

The Institute for Translational Genomics and Population Sciences, Department of Pediatrics and Los Angeles Biomedical Research Institute, Harbor-UCLA, Torrance, CA, USA.

Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of the protein. This includes ZNF529:p.K405X, which is associated with decreased low-density-lipoprotein (LDL) cholesterol (P = 1.3 × 10) without being associated with liver enzymes or non-fasting blood glucose. Silencing of ZNF529 in human hepatoma cells results in upregulation of LDL receptor and increased LDL uptake in the cells. This suggests that inhibition of ZNF529 or its gene product should be prioritized as a novel candidate drug target for treating dyslipidemia and associated CVD.
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http://dx.doi.org/10.1038/s41467-020-20086-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749177PMC
December 2020

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

Eur J Hum Genet 2021 Apr 28;29(4):615-624. Epub 2020 Nov 28.

Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, Helsinki, Finland.

Previous 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 Europeans (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.
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http://dx.doi.org/10.1038/s41431-020-00768-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114909PMC
April 2021

An expanded analysis framework for multivariate GWAS connects inflammatory biomarkers to functional variants and disease.

Eur J Hum Genet 2021 02 27;29(2):309-324. Epub 2020 Oct 27.

Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.

Multivariate methods are known to increase the statistical power to detect associations in the case of shared genetic basis between phenotypes. They have, however, lacked essential analytic tools to follow-up and understand the biology underlying these associations. We developed a novel computational workflow for multivariate GWAS follow-up analyses, including fine-mapping and identification of the subset of traits driving associations (driver traits). Many follow-up tools require univariate regression coefficients which are lacking from multivariate results. Our method overcomes this problem by using Canonical Correlation Analysis to turn each multivariate association into its optimal univariate Linear Combination Phenotype (LCP). This enables an LCP-GWAS, which in turn generates the statistics required for follow-up analyses. We implemented our method on 12 highly correlated inflammatory biomarkers in a Finnish population-based study. Altogether, we identified 11 associations, four of which (F5, ABO, C1orf140 and PDGFRB) were not detected by biomarker-specific analyses. Fine-mapping identified 19 signals within the 11 loci and driver trait analysis determined the traits contributing to the associations. A phenome-wide association study on the 19 representative variants from the signals in 176,899 individuals from the FinnGen study revealed 53 disease associations (p < 1 × 10). Several reported pQTLs in the 11 loci provided orthogonal evidence for the biologically relevant functions of the representative variants. Our novel multivariate analysis workflow provides a powerful addition to standard univariate GWAS analyses by enabling multivariate GWAS follow-up and thus promoting the advancement of powerful multivariate methods in genomics.
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http://dx.doi.org/10.1038/s41431-020-00730-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868371PMC
February 2021

MEPE loss-of-function variant associates with decreased bone mineral density and increased fracture risk.

Nat Commun 2020 10 23;11(1):4093. Epub 2020 Oct 23.

Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, 1500 E. Medical Center Dr., Ann Arbor, MI, 48109, USA.

A major challenge in genetic association studies is that most associated variants fall in the non-coding part of the human genome. We searched for variants associated with bone mineral density (BMD) after enriching the discovery cohort for loss-of-function (LoF) mutations by sequencing a subset of the Nord-Trøndelag Health Study, followed by imputation in the remaining sample (N = 19,705), and identified ten known BMD loci. However, one previously unreported variant, LoF mutation in MEPE, p.(Lys70IlefsTer26, minor allele frequency [MAF] = 0.8%), was associated with decreased ultradistal forearm BMD (P-value = 2.1 × 10), and increased osteoporosis (P-value = 4.2 × 10) and fracture risk (P-value = 1.6 × 10). The MEPE LoF association with BMD and fractures was further evaluated in 279,435 UK (MAF = 0.05%, heel bone estimated BMD P-value = 1.2 × 10, any fracture P-value = 0.05) and 375,984 Icelandic samples (MAF = 0.03%, arm BMD P-value = 0.12, forearm fracture P-value = 0.005). Screening for the MEPE LoF mutations before adulthood could potentially prevent osteoporosis and fractures due to the lifelong effect on BMD observed in the study. A key implication for precision medicine is that high-impact functional variants missing from the publicly available cosmopolitan panels could be clinically more relevant than polygenic risk scores.
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http://dx.doi.org/10.1038/s41467-020-17315-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585430PMC
October 2020

Exome sequencing and characterization of 49,960 individuals in the UK Biobank.

Nature 2020 10 21;586(7831):749-756. Epub 2020 Oct 21.

University of Michigan, Ann Arbor, MI, USA.

The UK Biobank is a prospective study of 502,543 individuals, combining extensive phenotypic and genotypic data with streamlined access for researchers around the world. Here we describe the release of exome-sequence data for the first 49,960 study participants, revealing approximately 4 million coding variants (of which around 98.6% have a frequency of less than 1%). The data include 198,269 autosomal predicted loss-of-function (LOF) variants, a more than 14-fold increase compared to the imputed sequence. Nearly all genes (more than 97%) had at least one carrier with a LOF variant, and most genes (more than 69%) had at least ten carriers with a LOF variant. We illustrate the power of characterizing LOF variants in this population through association analyses across 1,730 phenotypes. In addition to replicating established associations, we found novel LOF variants with large effects on disease traits, including PIEZO1 on varicose veins, COL6A1 on corneal resistance, MEPE on bone density, and IQGAP2 and GMPR on blood cell traits. We further demonstrate the value of exome sequencing by surveying the prevalence of pathogenic variants of clinical importance, and show that 2% of this population has a medically actionable variant. Furthermore, we characterize the penetrance of cancer in carriers of pathogenic BRCA1 and BRCA2 variants. Exome sequences from the first 49,960 participants highlight the promise of genome sequencing in large population-based studies and are now accessible to the scientific community.
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http://dx.doi.org/10.1038/s41586-020-2853-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759458PMC
October 2020

GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer.

Nat Commun 2020 08 7;11(1):3981. Epub 2020 Aug 7.

Center for Statistical Genetics and Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.

Thyroid stimulating hormone (TSH) is critical for normal development and metabolism. To better understand the genetic contribution to TSH levels, we conduct a GWAS meta-analysis at 22.4 million genetic markers in up to 119,715 individuals and identify 74 genome-wide significant loci for TSH, of which 28 are previously unreported. Functional experiments show that the thyroglobulin protein-altering variants P118L and G67S impact thyroglobulin secretion. Phenome-wide association analysis in the UK Biobank demonstrates the pleiotropic effects of TSH-associated variants and a polygenic score for higher TSH levels is associated with a reduced risk of thyroid cancer in the UK Biobank and three other independent studies. Two-sample Mendelian randomization using TSH index variants as instrumental variables suggests a protective effect of higher TSH levels (indicating lower thyroid function) on risk of thyroid cancer and goiter. Our findings highlight the pleiotropic effects of TSH-associated variants on thyroid function and growth of malignant and benign thyroid tumors.
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http://dx.doi.org/10.1038/s41467-020-17718-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414135PMC
August 2020

Use of a Polygenic Risk Score Improves Prediction of Myocardial Injury After Non-Cardiac Surgery.

Circ Genom Precis Med 2020 08 9;13(4):e002817. Epub 2020 Jun 9.

Department of Anesthesiology, Michigan Medicine, Ann Arbor (N.J.D., A.L., C.M.B., S.K., M.E., M.R.M.).

Background: While postoperative myocardial injury remains a major driver of morbidity and mortality, the ability to accurately identify patients at risk remains limited despite decades of clinical research. The role of genetic information in predicting myocardial injury after noncardiac surgery (MINS) remains unknown and requires large scale electronic health record and genomic data sets.

Methods: In this retrospective observational study of adult patients undergoing noncardiac surgery, we defined MINS as new troponin elevation within 30 days following surgery. To determine the incremental value of polygenic risk score (PRS) for coronary artery disease, we added the score to 3 models of MINS risk: revised cardiac risk index, a model comprised entirely of preoperative variables, and a model with combined preoperative plus intraoperative variables. We assessed performance without and with PRSs via area under the receiver operating characteristic curve and net reclassification index.

Results: Among 90 053 procedures across 40 498 genotyped individuals, we observed 429 cases with MINS (0.5%). PRS for coronary artery disease was independently associated with MINS for each multivariable model created (odds ratio=1.12 [95% CI, 1.02-1.24], =0.023 in the revised cardiac risk index-based model; odds ratio, 1.19 [95% CI, 1.07-1.31], =0.001 in the preoperative model; and odds ratio, 1.17 [95% CI, 1.06-1.30], =0.003 in the preoperative plus intraoperative model). The addition of clinical risk factors improved model discrimination. When PRS was included with preoperative and preoperative plus intraoperative models, up to 3.6% of procedures were shifted into a new outcome classification.

Conclusions: The addition of a PRS does not significantly improve discrimination but remains independently associated with MINS and improves goodness of fit. As genetic analysis becomes more common, clinicians will have an opportunity to use polygenic risk to predict perioperative complications. Further studies are necessary to determine if PRSs can inform MINS surveillance.
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http://dx.doi.org/10.1161/CIRCGEN.119.002817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442662PMC
August 2020

A Novel Variant in Gene Causes Extremely Low LDL-C Without Known Adverse Effects.

JACC Case Rep 2020 May 20;2(5):775-779. Epub 2020 May 20.

University of Michigan, Michigan Medicine, Ann Arbor, Michigan.

A novel frameshift variant was identified in that segregates in a dominant manner with low levels of low-density lipoprotein cholesterol. Affected family members show no apparent clinical complications. There is no consensus regarding clinical management, and the long-term consequences of low levels of low-density lipoprotein cholesterol remain unknown. ().
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http://dx.doi.org/10.1016/j.jaccas.2020.03.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301695PMC
May 2020

Polygenic Hyperlipidemias and Coronary Artery Disease Risk.

Circ Genom Precis Med 2020 04 10;13(2):e002725. Epub 2020 Mar 10.

Institute for Molecular Medicine Finland, Helsinki Institute of Life Science (HiLIFE) (P.R., J.T.R., N.J.M., Y.F., J.L., C.B., I.S., T.K., A.S.H., P.P., E.W., T.T., M.P., A.P., S.R.), University of Helsinki, Helsinki, Finland.

Background: 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 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.
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http://dx.doi.org/10.1161/CIRCGEN.119.002725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176338PMC
April 2020

Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length.

Am J Hum Genet 2020 03 27;106(3):389-404. Epub 2020 Feb 27.

Department of Cardiovascular Sciences, University of Leicester, LE3 9QP, United Kingdom; NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, LE3 9QP, United Kingdom.

Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.
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http://dx.doi.org/10.1016/j.ajhg.2020.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058826PMC
March 2020

Mitochondrial genome-wide association study of migraine - the HUNT Study.

Cephalalgia 2020 05 14;40(6):625-634. Epub 2020 Feb 14.

Research and Communication Unit for Musculoskeletal Health, Division of Clinical Neuroscience, Oslo University Hospital, Ullevaal, Oslo, Norway.

Background: Variation in mitochondrial DNA (mtDNA) has been indicated in migraine pathogenesis, but genetic studies to date have focused on candidate variants, with sparse findings. We aimed to perform the first mitochondrial genome-wide association study of migraine, examining both single variants and mitochondrial haplogroups.

Methods: In total, 71,860 participants from the population-based Nord-Trøndelag Health Study were genotyped. We excluded samples not passing quality control for nuclear genotypes, in addition to samples with low call rate and closely maternally related. We analysed 775 mitochondrial DNA variants in 4021 migraine cases and 14,288 headache-free controls, using logistic regression. In addition, we analysed 3831 cases and 13,584 controls who could be reliably assigned to a mitochondrial haplogroup. Lastly, we attempted to replicate previously reported mitochondrial DNA candidate variants.

Results: Neither of the mitochondrial variants or haplogroups were associated with migraine. In addition, none of the previously reported mtDNA candidate variants replicated in our data.

Conclusions: Our findings do not support a major role of mitochondrial genetic variation in migraine pathophysiology, but a larger sample is needed to detect rare variants and future studies should also examine heteroplasmic variation, epigenetic changes and copy-number variation.
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http://dx.doi.org/10.1177/0333102420906835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243449PMC
May 2020

Geographic Variation and Bias in the Polygenic Scores of Complex Diseases and Traits in Finland.

Am J Hum Genet 2019 06 30;104(6):1169-1181. Epub 2019 May 30.

Institute for Molecular Medicine Finland, Helsinki Institute of Life Sciences, University of Helsinki, Helsinki 00014, Finland; Department of Public Health, University of Helsinki, Helsinki 00014, Finland; Helsinki Institute for Information Technology and Department of Mathematics and Statistics, University of Helsinki, Helsinki 00014, Finland. Electronic address:

Polygenic scores (PSs) are becoming a useful tool to identify individuals with high genetic risk for complex diseases, and several projects are currently testing their utility for translational applications. It is also tempting to use PSs to assess whether genetic variation can explain a part of the geographic distribution of a phenotype. However, it is not well known how the population genetic properties of the training and target samples affect the geographic distribution of PSs. Here, we evaluate geographic differences, and related biases, of PSs in Finland in a geographically well-defined sample of 2,376 individuals from the National FINRISK study. First, we detect geographic differences in PSs for coronary artery disease (CAD), rheumatoid arthritis, schizophrenia, waist-hip ratio (WHR), body-mass index (BMI), and height, but not for Crohn disease or ulcerative colitis. Second, we use height as a model trait to thoroughly assess the possible population genetic biases in PSs and apply similar approaches to the other phenotypes. Most importantly, we detect suspiciously large accumulations of geographic differences for CAD, WHR, BMI, and height, suggesting bias arising from the population's genetic structure rather than from a direct genotype-phenotype association. This work demonstrates how sensitive the geographic patterns of current PSs are for small biases even within relatively homogeneous populations and provides simple tools to identify such biases. A thorough understanding of the effects of population genetic structure on PSs is essential for translational applications of PSs.
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http://dx.doi.org/10.1016/j.ajhg.2019.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562021PMC
June 2019

Sex-specific and pleiotropic effects underlying kidney function identified from GWAS meta-analysis.

Nat Commun 2019 04 23;10(1):1847. Epub 2019 Apr 23.

Department of Internal Medicine: Cardiology, University of Michigan, Ann Arbor, 48109, MI, USA.

Chronic kidney disease (CKD) is a growing health burden currently affecting 10-15% of adults worldwide. Estimated glomerular filtration rate (eGFR) as a marker of kidney function is commonly used to diagnose CKD. We analyze eGFR data from the Nord-Trøndelag Health Study and Michigan Genomics Initiative and perform a GWAS meta-analysis with public summary statistics, more than doubling the sample size of previous meta-analyses. We identify 147 loci (53 novel) associated with eGFR, including genes involved in transcriptional regulation, kidney development, cellular signaling, metabolism, and solute transport. Additionally, sex-stratified analysis identifies one locus with more significant effects in women than men. Using genetic risk scores constructed from these eGFR meta-analysis results, we show that associated variants are generally predictive of CKD with only modest improvements in detection compared with other known clinical risk factors. Collectively, these results yield additional insight into the genetic factors underlying kidney function and progression to CKD.
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http://dx.doi.org/10.1038/s41467-019-09861-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478837PMC
April 2019

New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries.

Nat Genet 2019 03 25;51(3):481-493. Epub 2019 Feb 25.

Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function-associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.
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http://dx.doi.org/10.1038/s41588-018-0321-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397078PMC
March 2019

Risk Factors for Early-Onset Ischemic Stroke: A Case-Control Study.

J Am Heart Assoc 2018 11;7(21):e009774

1 Clinical Neurosciences University of Helsinki and Department of Neurology, Helsinki University Hospital Helsinki Finland.

Background Recent studies have shown an increasing prevalence of vascular risk factors in young adults with ischemic stroke ( IS ). However, the strength of the association between all vascular risk factors and early-onset IS has not been fully established. Methods and Results We compared 961 patients with a first-ever IS at 25 to 49 years to 1403 frequency-matched stroke-free controls from a population-based cohort study ( FINRISK ). Assessed risk factors included an active malignancy, atrial fibrillation, cardiovascular disease, current smoking status, a family history of stroke, high low-density lipoprotein cholesterol, high triglycerides, low high-density lipoprotein cholesterol, hypertension, and type 1 and type 2 diabetes mellitus. We performed subgroup analyses based on age, sex, and IS etiology. In a fully adjusted multivariable logistic regression analysis, significant risk factors for IS consisted of atrial fibrillation (odds ratio [OR], 10.43; 95% confidence interval [ CI ], 2.33-46.77], cardiovascular disease (OR, 8.01; 95% CI , 3.09-20.78), type 1 diabetes mellitus (OR, 6.72; 95% CI , 3.15-14.33), type 2 diabetes mellitus (OR, 2.31; 95% CI , 1.35-3.95), low high-density lipoprotein cholesterol (OR, 1.81; 95% CI , 1.37-2.40), current smoking status (OR, 1.81; 95% CI , 1.50-2.17), hypertension (OR, 1.43; 95% CI , 1.17-1.75), and a family history of stroke (OR, 1.37; 95% CI , 1.04-1.82). High low-density lipoprotein cholesterol exhibited an inverse association with IS . In the subgroup analyses, the most consistent associations appeared for current smoking status and type 1 diabetes mellitus. Conclusions Our study establishes the associations between 11 vascular risk factors and early-onset IS , among which atrial fibrillation, cardiovascular disease, and both type 1 and 2 diabetes mellitus in particular showed strong associations.
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http://dx.doi.org/10.1161/JAHA.118.009774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404210PMC
November 2018

Publisher Correction: Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries.

Nat Commun 2018 08 23;9(1):3493. Epub 2018 Aug 23.

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.

The original version of this article contained an error in the name of the author Ramachandran S. Vasan, which was incorrectly given as Vasan S. Ramachandran. This has now been corrected in both the PDF and HTML versions of the article.
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http://dx.doi.org/10.1038/s41467-018-05975-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107495PMC
August 2018

Deep-coverage whole genome sequences and blood lipids among 16,324 individuals.

Nat Commun 2018 08 23;9(1):3391. Epub 2018 Aug 23.

School of Medicine, University of Maryland, Baltimore, MD, 21201, USA.

Large-scale deep-coverage whole-genome sequencing (WGS) is now feasible and offers potential advantages for locus discovery. We perform WGS in 16,324 participants from four ancestries at mean depth >29X and analyze genotypes with four quantitative traits-plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides. Common variant association yields known loci except for few variants previously poorly imputed. Rare coding variant association yields known Mendelian dyslipidemia genes but rare non-coding variant association detects no signals. A high 2M-SNP LDL-C polygenic score (top 5th percentile) confers similar effect size to a monogenic mutation (~30 mg/dl higher for each); however, among those with severe hypercholesterolemia, 23% have a high polygenic score and only 2% carry a monogenic mutation. At these sample sizes and for these phenotypes, the incremental value of WGS for discovery is limited but WGS permits simultaneous assessment of monogenic and polygenic models to severe hypercholesterolemia.
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http://dx.doi.org/10.1038/s41467-018-05747-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107638PMC
August 2018

Biobank-driven genomic discovery yields new insight into atrial fibrillation biology.

Nat Genet 2018 09 30;50(9):1234-1239. Epub 2018 Jul 30.

Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.

To identify genetic variation underlying atrial fibrillation, the most common cardiac arrhythmia, we performed a genome-wide association study of >1,000,000 people, including 60,620 atrial fibrillation cases and 970,216 controls. We identified 142 independent risk variants at 111 loci and prioritized 151 functional candidate genes likely to be involved in atrial fibrillation. Many of the identified risk variants fall near genes where more deleterious mutations have been reported to cause serious heart defects in humans (GATA4, MYH6, NKX2-5, PITX2, TBX5), or near genes important for striated muscle function and integrity (for example, CFL2, MYH7, PKP2, RBM20, SGCG, SSPN). Pathway and functional enrichment analyses also suggested that many of the putative atrial fibrillation genes act via cardiac structural remodeling, potentially in the form of an 'atrial cardiomyopathy', either during fetal heart development or as a response to stress in the adult heart.
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http://dx.doi.org/10.1038/s41588-018-0171-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6530775PMC
September 2018

Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries.

Nat Commun 2018 07 4;9(1):2606. Epub 2018 Jul 4.

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.

Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans.
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http://dx.doi.org/10.1038/s41467-018-04668-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6031652PMC
July 2018

Common Variant Burden Contributes to the Familial Aggregation of Migraine in 1,589 Families.

Neuron 2018 05 3;98(4):743-753.e4. Epub 2018 May 3.

National Institute for Health and Welfare, Helsinki, Finland.

Complex traits, including migraine, often aggregate in families, but the underlying genetic architecture behind this is not well understood. The aggregation could be explained by rare, penetrant variants that segregate according to Mendelian inheritance or by the sufficient polygenic accumulation of common variants, each with an individually small effect, or a combination of the two hypotheses. In 8,319 individuals across 1,589 migraine families, we calculated migraine polygenic risk scores (PRS) and found a significantly higher common variant burden in familial cases (n = 5,317, OR = 1.76, 95% CI = 1.71-1.81, p = 1.7 × 10) compared to population cases from the FINRISK cohort (n = 1,101, OR = 1.32, 95% CI = 1.25-1.38, p = 7.2 × 10). The PRS explained 1.6% of the phenotypic variance in the population cases and 3.5% in the familial cases (including 2.9% for migraine without aura, 5.5% for migraine with typical aura, and 8.2% for hemiplegic migraine). The results demonstrate a significant contribution of common polygenic variation to the familial aggregation of migraine.
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http://dx.doi.org/10.1016/j.neuron.2018.04.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5967411PMC
May 2018

Electronic health records: the next wave of complex disease genetics.

Hum Mol Genet 2018 05;27(R1):R14-R21

Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.

The combination of electronic health records (EHRs) with genetic data has ushered in the next wave of complex disease genetics. Population-based biobanks and other large cohorts provide sufficient sample sizes to identify novel genetic associations across the hundreds to thousands of phenotypes gleaned from EHRs. In this review, we summarize the current state of these EHR-linked biobanks, explore ongoing methods development in the field and highlight recent discoveries of genetic associations. We enumerate the many existing biobanks with EHRs linked to genetic data, many of which are available to researchers via application and contain sample sizes >50 000. We also discuss the computational and statistical considerations for analysis of such large datasets including mixed models, phenotype curation and cloud computing. Finally, we demonstrate how genome-wide association studies and phenome-wide association studies have identified novel genetic findings for complex diseases, specifically cardiometabolic traits. As more researchers employ innovative hypotheses and analysis approaches to study EHR-linked biobanks, we anticipate a richer understanding of the genetic etiology of complex diseases.
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http://dx.doi.org/10.1093/hmg/ddy081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946915PMC
May 2018

Genome-wide association study in Finnish twins highlights the connection between nicotine addiction and neurotrophin signaling pathway.

Addict Biol 2019 05 13;24(3):549-561. Epub 2018 Mar 13.

Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland.

The heritability of nicotine dependence based on family studies is substantial. Nevertheless, knowledge of the underlying genetic architecture remains meager. Our aim was to identify novel genetic variants responsible for interindividual differences in smoking behavior. We performed a genome-wide association study on 1715 ever smokers ascertained from the population-based Finnish Twin Cohort enriched for heavy smoking. Data imputation used the 1000 Genomes Phase I reference panel together with a whole genome sequence-based Finnish reference panel. We analyzed three measures of nicotine addiction-smoking quantity, nicotine dependence and nicotine withdrawal. We annotated all genome-wide significant SNPs for their functional potential. First, we detected genome-wide significant association on 16p12 with smoking quantity (P = 8.5 × 10 ), near CLEC19A. The lead-SNP stands 22 kb from a binding site for NF-κB transcription factors, which play a role in the neurotrophin signaling pathway. However, the signal was not replicated in an independent Finnish population-based sample, FINRISK (n = 6763). Second, nicotine withdrawal showed association on 2q21 in an intron of TMEM163 (P = 2.1 × 10 ), and on 11p15 (P = 6.6 × 10 ) in an intron of AP2A2, and P = 4.2 × 10 for a missense variant in MUC6, both involved in the neurotrophin signaling pathway). Third, association was detected on 3p22.3 for maximum number of cigarettes smoked per day (P = 3.1 × 10 ) near STAC. Associating CLEC19A and TMEM163 SNPs were annotated to influence gene expression or methylation. The neurotrophin signaling pathway has previously been associated with smoking behavior. Our findings further support the role in nicotine addiction.
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http://dx.doi.org/10.1111/adb.12618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519128PMC
May 2019
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