TY  - JOUR
AB  - BACKGROUND: The immune system's role in ST-segment-elevated myocardial infarction (STEMI) remains poorly characterized but is an important driver of recurrent cardiovascular events. While anti-inflammatory drugs show promise in reducing recurrence risk, their broad immune system impairment may induce severe side effects. To overcome these challenges, a nuanced understanding of the immune response to STEMI is needed. METHODS: For this, we compared peripheral blood mononuclear single-cell RNA-sequencing (scRNA-seq) and plasma protein expression over time (hospital admission, 24 hours, and 6-8 weeks post-STEMI) in 38 patients and 38 controls (95 995 diseased and 33 878 control peripheral blood mononuclear cells). RESULTS: Compared with controls, classical monocytes were increased and CD56dim natural killer cells were decreased in patients with STEMI at admission and persisted until 24 hours post-STEMI. The largest gene expression changes were observed in monocytes, associating with changes in toll-like receptor, interferon, and interleukin signaling activity. Finally, a targeted cardiovascular biomarker panel revealed expression changes in 33/92 plasma proteins post-STEMI. Interestingly, interleukin-6R, MMP9 (matrix metalloproteinase-9), and LDLR (low-density lipoprotein receptor) were affected by coronary artery disease-associated genetic risk variation, disease status, and time post-STEMI, indicating the importance of considering these aspects when defining potential future therapies. CONCLUSIONS: Our analyses revealed the immunologic pathways disturbed by STEMI, specifying affected cell types and disease stages. Additionally, we provide insights into patients expected to benefit most from anti-inflammatory treatments by identifying the genetic variants and disease stage at which these variants affect the outcome of these (drug-targeted) pathways. These findings advance our knowledge of the immune response post-STEMI and provide guidance for future therapeutic studies.
AU  - van Blokland, I.V.*
AU  - Oelen, R.*
AU  - Groot, H.E.*
AU  - Benjamins, J.W.*
AU  - Pekayvaz, K.*
AU  - Losert, C.
AU  - Knottenberg, V.*
AU  - Heinig, M.
AU  - Nicolai, L.*
AU  - Stark, K.*
AU  - van der Harst, P.*
AU  - Franke, L.*
AU  - van der Wijst, M.G.P.*
C1  - 70685
C2  - 55814
TI  - Single-cell dissection of the immune response after acute myocardial infarction.
JO  - Circ. Genom. Precis. Med.
VL  - 17
IS  - 3
PY  - 2024
SN  - 2574-8300
ER  - 

TY  - JOUR
AB  - BACKGROUND: Lp(a) (lipoprotein [a]) is a highly atherogenic lipoprotein strongly associated with coronary artery disease (CAD). Lp(a) concentrations are chiefly determined genetically. Investigation of large pedigrees with extreme Lp(a) using modern whole-genome approaches may unravel the genetic determinants underpinning this pathological phenotype. METHODS: A large family characterized by high Lp(a) and increased CAD incidence was recruited by cascade screening. Plasma lipids, lipoproteins, and apolipoproteins concentrations, as well as the size of apo(a) isoforms, were determined enzymatically by high-resolution mass spectrometry and Western blot, respectively. Whole-exome sequencing was performed to search for rare defects in modifier genes. Genetic risk scores (GRS) for Lp(a) and CAD were calculated and their discriminative power was assessed. RESULTS: Seventeen individuals displayed extreme Lp(a) levels including 6 with CAD. Whole-exome sequencing showed no hint for genetic defects outside the LPA locus. The extreme Lp(a) phenotype segregated with the presence of a short apo(a) isoform containing 21 Kringle IV domains. This allele was characterized by the presence of three rare strongly Lp(a) increasing single nucleotide polymorphisms and a significantly increased load of oxidized phospholipids per Lp(a) particle. An Lp(a) GRS consisting of 48 single nucleotide polymorphisms that represent 2001 genome-wide significant LPA single nucleotide polymorphisms, efficiently captured the hyper-Lp(a) phenotype and discriminated affected and nonaffected individuals with great accuracy. The genome-wide GRS for CAD, encompassing 6.6 million single nucleotide polymorphisms, was very high for most family members (>97.5 percentile of the reference population), but this observation was no longer valid when the contribution of the LPA locus was omitted. CONCLUSIONS: High-Lp(a) phenotypes can be successfully captured using the Lp(a) GRS even among closely related family members. In hyper-Lp(a) individuals, LPA can be a major locus driving a very high CAD GRS. This underpins the large contribution of the LPA locus to the cardiovascular genetic risk in families.
AU  - Coassin, S.*
AU  - Chemello, K.*
AU  - Khantalin, I.*
AU  - Forer, L.*
AU  - Döttelmayer, P.*
AU  - Schönherr, S.*
AU  - Grüneis, R.*
AU  - Chong-Hong-Fong, C.*
AU  - Nativel, B.*
AU  - Ramin-Mangata, S.*
AU  - Gallo, A.*
AU  - Roche, M.*
AU  - Mühlegger, B.*
AU  - Gieger, C.
AU  - Peters, A.
AU  - Zschocke, J.*
AU  - Marimoutou, C.*
AU  - Meilhac, O.*
AU  - Lamina, C.*
AU  - Kronenberg, F.*
AU  - Blanchard, V.*
AU  - Lambert, G.*
C1  - 64236
C2  - 52028
TI  - Genome-wide characterization of a highly penetrant form of hyperlipoproteinemia associated with genetically elevated cardiovascular Risk.
JO  - Circ. Genom. Precis. Med.
VL  - 15
IS  - 2
PY  - 2022
SN  - 2574-8300
ER  - 

TY  - JOUR
AB  - BACKGROUND: Peripheral artery disease (PAD) affects >200 million people worldwide and is associated with high mortality and morbidity. We sought to identify genomic variants associated with PAD overall and in the contexts of diabetes and smoking status. METHODS: We identified genetic variants associated with PAD and then meta-analyzed with published summary statistics from the Million Veterans Program and UK Biobank to replicate their findings. Next, we ran stratified genome-wide association analysis in ever smokers, never smokers, individuals with diabetes, and individuals with no history of diabetes and corresponding interaction analyses, to identify variants that modify the risk of PAD by diabetic or smoking status. RESULTS: We identified 5 genome-wide significant (Passociation ≤5×10-8) associations with PAD in 449 548 (Ncases=12 086) individuals of European ancestry near LPA (lipoprotein [a]), CDKN2BAS1 (CDKN2B antisense RNA 1), SH2B3 (SH2B adaptor protein 3) - PTPN11 (protein tyrosine phosphatase non-receptor type 11), HDAC9 (histone deacetylase 9), and CHRNA3 (cholinergic receptor nicotinic alpha 3 subunit) loci (which overlapped previously reported associations). Meta-analysis with variants previously associated with PAD showed that 18 of 19 published variants remained genome-wide significant. In individuals with diabetes, rs116405693 at the CCSER1 (coiled-coil serine rich protein 1) locus was associated with PAD (odds ratio [95% CI], 1.51 [1.32-1.74], Pdiabetes=2.5×10-9, Pinteractionwithdiabetes=5.3×10-7). Furthermore, in smokers, rs12910984 at the CHRNA3 locus was associated with PAD (odds ratio [95% CI], 1.15 [1.11-1.19], Psmokers=9.3×10-10, Pinteractionwithsmoking=3.9×10-5). CONCLUSIONS: Our analyses confirm the published genetic associations with PAD and identify novel variants that may influence susceptibility to PAD in the context of diabetes or smoking status.
AU  - van Zuydam, N.R.*
AU  - Stiby, A.*
AU  - Abdalla, M.*
AU  - Austin, E.*
AU  - Dahlström, E.H.*
AU  - McLachlan, S.*
AU  - Vlachopoulou, E.*
AU  - Ahlqvist, E.*
AU  - Di Liao, C.*
AU  - Sandholm, N.*
AU  - Forsblom, C.*
AU  - Mahajan, A.*
AU  - Robertson, N.R.*
AU  - Rayner, N.W.*
AU  - Lindholm, E.*
AU  - Sinisalo, J.*
AU  - Perola, M.*
AU  - Kallio, M.*
AU  - Weiss, E.*
AU  - Price, J.*
AU  - Paterson, A.*
AU  - Klein, B.*
AU  - Salomaa, V.*
AU  - Palmer, C.N.A.*
AU  - Groop, P.H.*
AU  - Groop, L.*
AU  - McCarthy, M.I.*
AU  - de Andrade, M.*
AU  - Morris, A.P.*
AU  - Hopewell, J.C.*
AU  - Colhoun, H.M.*
AU  - Kullo, I.J.*
AU  - SUMMIT consortium (Thorand, B.)
C1  - 63513
C2  - 51351
TI  - Genome-wide association study of peripheral artery disease.
JO  - Circ. Genom. Precis. Med.
VL  - 14
IS  - 5
PY  - 2021
SN  - 2574-8300
ER  - 

TY  - JOUR
AB  - Background: DNA methylation patterns associated with habitual diet have not been well studied. Methods: Diet quality was characterized using a Mediterranean-style diet score and the Alternative Healthy Eating Index score. We conducted ethnicity-specific and trans-ethnic epigenome-wide association analyses for diet quality and leukocyte-derived DNA methylation at over 400 000 CpGs (cytosine-guanine dinucleotides) in 5 population-based cohorts including 6662 European ancestry, 2702 African ancestry, and 360 Hispanic ancestry participants. For diet-associated CpGs identified in epigenome-wide analyses, we conducted Mendelian randomization (MR) analysis to examine their relations to cardiovascular disease risk factors and examined their longitudinal associations with all-cause mortality. Results: We identified 30 CpGs associated with either Mediterranean-style diet score or Alternative Healthy Eating Index, or both, in European ancestry participants. Among these CpGs, 12 CpGs were significantly associated with all-cause mortality (Bonferroni correctedP<1.6x10(-3)). Hypermethylation of cg18181703 (SOCS3) was associated with higher scores of both Mediterranean-style diet score and Alternative Healthy Eating Index and lower risk for all-cause mortality (P=5.7x10(-15)). Ten additional diet-associated CpGs were nominally associated with all-cause mortality (P<0.05). MR analysis revealed 8 putatively causal associations for 6 CpGs with 4 cardiovascular disease risk factors (body mass index, triglycerides, high-density lipoprotein cholesterol concentrations, and type 2 diabetes mellitus; Bonferroni corrected MRP<4.5x10(-4)). For example, hypermethylation of cg11250194 (FADS2) was associated with lower triglyceride concentrations (MR,P=1.5x10(-14)).and hypermethylation of cg02079413 (SNORA54;NAP1L4) was associated with body mass index (corrected MR,P=1x10(-6)). Conclusions: Habitual diet quality was associated with differential peripheral leukocyte DNA methylation levels of 30 CpGs, most of which were also associated with multiple health outcomes, in European ancestry individuals. These findings demonstrate that integrative genomic analysis of dietary information may reveal molecular targets for disease prevention and treatment.
AU  - Ma, J.*
AU  - Rebholz, C.M.*
AU  - Braun, K.V.E.*
AU  - Reynolds, L.M.*
AU  - Aslibekyan, S.*
AU  - Xia, R.*
AU  - Biligowda, N.G.*
AU  - Huan, T.*
AU  - Liu, C.*
AU  - Mendelson, M.M.*
AU  - Joehanes, R.*
AU  - Hu, E.A.*
AU  - Vitolins, M.Z.*
AU  - Wood, A.C.*
AU  - Lohman, K.*
AU  - Ochoa-Rosales, C.*
AU  - van Meurs, J.*
AU  - Uitterlinden, A.*
AU  - Liu, Y.*
AU  - Elhadad, M.A.
AU  - Heier, M.*
AU  - Waldenberger, M.
AU  - Peters, A.
AU  - Colicino, E.*
AU  - Whitsel, E.A.*
AU  - Baldassari, A.*
AU  - Gharib, S.A.*
AU  - Sotoodehnia, N.*
AU  - Brody, J.A.*
AU  - Sitlani, C.M.*
AU  - Tanaka, T.*
AU  - Hill, W.D.*
AU  - Corley, J.*
AU  - Deary, I.J.*
AU  - Zhang, Y.*
AU  - Schöttker, B.*
AU  - Brenner, H.*
AU  - Walker, M.E.*
AU  - Ye, S.*
AU  - Nguyen, S.*
AU  - Pankow, J.*
AU  - Demerath, E.W.*
AU  - Zheng, Y.*
AU  - Hou, L.*
AU  - Liang, L.*
AU  - Lichtenstein, A.H.*
AU  - Hu, F.B.*
AU  - Fornage, M.*
AU  - Voortman, T.*
AU  - Levy, D.*
C1  - 59972
C2  - 48463
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
TI  - Whole blood DNA methylation signatures of diet are associated with cardiovascular disease risk factors and all-cause mortality.
JO  - Circ. Genom. Precis. Med.
VL  - 13
IS  - 4
PB  - Lippincott Williams & Wilkins
PY  - 2020
SN  - 2574-8300
ER  - 

TY  - JOUR
AB  - Background: Coronary artery disease (CAD) is accelerated in subjects with type 2 diabetes mellitus (T2D). Methods: To test whether this reflects differential genetic influences on CAD risk in subjects with T2D, we performed a systematic assessment of genetic overlap between CAD and T2D in 66 643 subjects (27 708 with CAD and 24 259 with T2D). Variants showing apparent association with CAD in stratified analyses or evidence of interaction were evaluated in a further 117 787 subjects (16 694 with CAD and 11 537 with T2D). Results: None of the previously characterized CAD loci was found to have specific effects on CAD in T2D individuals, and a genome-wide interaction analysis found no new variants for CAD that could be considered T2D specific. When we considered the overall genetic correlations between CAD and its risk factors, we found no substantial differences in these relationships by T2D background. Conclusions: This study found no evidence that the genetic architecture of CAD differs in those with T2D compared with those without T2D.
AU  - Van Zuydam, N.R.*
AU  - Ladenvall, C.*
AU  - Voight, B.F.*
AU  - Strawbridge, R.J.*
AU  - Fernandez-Tajes, J.*
AU  - Rayner, N.W.*
AU  - Robertson, N.R.*
AU  - Mahajan, A.*
AU  - Vlachopoulou, E.*
AU  - Goel, A.*
AU  - Kleber, M.E.*
AU  - Nelson, C.P.*
AU  - Kwee, L.C.*
AU  - Esko, T.*
AU  - Mihailov, E.*
AU  - Mägi, R.*
AU  - Milani, L.*
AU  - Fischer, K.*
AU  - Kanoni, S.*
AU  - Kumar, J.*
AU  - Song, C.*
AU  - Hartiala, J.A.*
AU  - Pedersen, N.L.*
AU  - Perola, M.*
AU  - Gieger, C.
AU  - Peters, A.
AU  - Qu, L.*
AU  - Willems, S.M.*
AU  - Doney, A.S.F.*
AU  - Morris, A.D.*
AU  - Zheng, Y.*
AU  - Sesti, G.*
AU  - Hu, F.B.*
AU  - Qi, L.*
AU  - Laakso, M.*
AU  - Thorsteinsdottir, U.*
AU  - Grallert, H.
AU  - van Duijn, C.M.*
AU  - Reilly, M.P.*
AU  - Ingelsson, E.*
AU  - Deloukas, P.*
AU  - Kathiresan, S.*
AU  - Metspalu, A.*
AU  - Shah, S.H.*
AU  - Sinisalo, J.*
AU  - Salomaa, V.*
AU  - Hamsten, A.*
AU  - Samani, N.J.*
AU  - Marz, W.*
AU  - Hazen, S.L.*
AU  - Watkins, H.*
AU  - Saleheen, D.*
AU  - Colhoun, H.M.*
AU  - Groop, L.*
AU  - McCarthy, M.I.*
AU  - SUMMIT Steering Committee
AU  - CARDIOGRAMplusC4D Steering Committee (Thorand, B.)
C1  - 60858
C2  - 49627
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
SP  - 640-648
TI  - Genetic predisposition to coronary artery disease in type 2 diabetes mellitus.
JO  - Circ. Genom. Precis. Med.
VL  - 13
IS  - 6
PB  - Lippincott Williams & Wilkins
PY  - 2020
SN  - 2574-8300
ER  - 

TY  - JOUR
AB  - BACKGROUND: The P-wave duration (PWD) is an electrocardiographic measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome-chip data to examine the associations between common and rare variants with PWD. METHODS: Fifteen studies comprising 64 440 individuals (56 943 European, 5681 African, 1186 Hispanic, 630 Asian) and ≈230 000 variants were used to examine associations with maximum PWD across the 12-lead ECG. Meta-analyses summarized association results for common variants; gene-based burden and sequence kernel association tests examined low-frequency variant-PWD associations. Additionally, we examined the associations between PWD loci and AF using previous AF genome-wide association studies. RESULTS: We identified 21 common and low-frequency genetic loci (14 novel) associated with maximum PWD, including several AF loci (TTN, CAND2, SCN10A, PITX2, CAV1, SYNPO2L, SOX5, TBX5, MYH6, RPL3L). The top variants at known sarcomere genes (TTN, MYH6) were associated with longer PWD and increased AF risk. However, top variants at other loci (eg, PITX2 and SCN10A) were associated with longer PWD but lower AF risk. CONCLUSIONS: Our results highlight multiple novel genetic loci associated with PWD, and underscore the shared mechanisms of atrial conduction and AF. Prolonged PWD may be an endophenotype for several different genetic mechanisms of AF.
AU  - Weng, L.C.*
AU  - Hall, A.W.*
AU  - Choi, S.H.*
AU  - Jurgens, S.J.*
AU  - Haessler, J.*
AU  - Bihlmeyer, N.A.*
AU  - Grarup, N.*
AU  - Lin, H.*
AU  - Teumer, A.*
AU  - Li-Gao, R.*
AU  - Yao, J.*
AU  - Guo, X.*
AU  - Brody, J.A.*
AU  - Müller-Nurasyid, M.
AU  - Schramm, K.
AU  - Verweij, N.*
AU  - van den Berg, M.E.*
AU  - van Setten, J.*
AU  - Isaacs, A.*
AU  - Ramírez, J.*
AU  - Warren, H.R.*
AU  - Padmanabhan, S.*
AU  - Kors, J.A.*
AU  - de Boer, R.A.*
AU  - van der Meer, P.*
AU  - Sinner, M.F.*
AU  - Waldenberger, M.
AU  - Psaty, B.M.*
AU  - Taylor, K.D.*
AU  - Völker, U.*
AU  - Kanters, J.K.*
AU  - Li, M.*
AU  - Alonso, A.*
AU  - Perez, M.V.*
AU  - Vaartjes, I.*
AU  - Bots, M.L.*
AU  - Huang, P.L.*
AU  - Heckbert, S.R.*
AU  - Lin, H.J.*
AU  - Kornej, J.*
AU  - Munroe, P.B.*
AU  - van Duijn, C.M.*
AU  - Asselbergs, F.W.*
AU  - Stricker, B.H.*
AU  - van der Harst, P.*
AU  - Kääb, S.*
AU  - Peters, A.
AU  - Sotoodehnia, N.*
AU  - Rotter, J.I.*
AU  - Mook-Kanamori, D.O.*
AU  - Dörr, M.*
AU  - Felix, S.B.*
AU  - Linneberg, A.*
AU  - Hansen, T.*
AU  - Arking, D.E.*
AU  - Kooperberg, C.*
AU  - Benjamin, E.J.*
AU  - Lunetta, K.L.*
AU  - Ellinor, P.T.*
AU  - Lubitz, S.A.*
C1  - 60425
C2  - 49450
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
SP  - 387-395
TI  - Genetic determinants of electrocardiographic P-wave duration and relation to atrial fibrillation.
JO  - Circ. Genom. Precis. Med.
VL  - 13
IS  - 5
PB  - Lippincott Williams & Wilkins
PY  - 2020
SN  - 2574-8300
ER  - 

TY  - JOUR
AB  - Background: Brugada syndrome (BrS) is characterized by the type 1 Brugada ECG pattern. Pathogenic rare variants in SCN5A (mutations) are identified in 20% of BrS families in whom incomplete penetrance and genotype-negative phenotype-positive individuals are observed. E1784K-SCN5A is the most common SCN5A mutation identified. We determined the association of a BrS genetic risk score (BrS-GRS) and SCN5A mutation type on BrS phenotype in BrS families with SCN5A mutations. Methods: Subjects with a spontaneous type 1 pattern or positive/negative drug challenge from cohorts harboring SCN5A mutations were recruited from 16 centers (n=312). Single nucleotide polymorphisms previously associated with BrS at genome-wide significance were studied in both cohorts: rs11708996, rs10428132, and rs9388451. An additive linear genetic model for the BrS-GRS was assumed (6 single nucleotide polymorphism risk alleles). Results: In the total population (n=312), BrS-GRS ≥4 risk alleles yielded an odds ratio of 4.15 for BrS phenotype ([95% CI, 1.45-11.85]; P=0.0078). Among SCN5A-positive individuals (n=258), BrS-GRS ≥4 risk alleles yielded an odds ratio of 2.35 ([95% CI, 0.89-6.22]; P=0.0846). In SCN5A-negative relatives (n=54), BrS-GRS ≥4 alleles yielded an odds ratio of 22.29 ([95% CI, 1.84-269.30]; P=0.0146). Among E1784K-SCN5A positive family members (n=79), hosting ≥4 risk alleles gave an odds ratio=5.12 ([95% CI, 1.93-13.62]; P=0.0011). Conclusions: Common genetic variation is associated with variable expressivity of BrS phenotype in SCN5A families, explaining in part incomplete penetrance and genotype-negative phenotype-positive individuals. SCN5A mutation genotype and a BrS-GRS associate with BrS phenotype, but the strength of association varies according to presence of a SCN5A mutation and severity of loss of function.
AU  - Wijeyeratne, Y.D.*
AU  - Tanck, M.W.*
AU  - Mizusawa, Y.*
AU  - Batchvarov, V.*
AU  - Barc, J.*
AU  - Crotti, L.*
AU  - Bos, J.M.*
AU  - Tester, D.J.*
AU  - Muir, A.M.*
AU  - Veltmann, C.*
AU  - Ohno, S.*
AU  - Page, S.P.*
AU  - Galvin, J.*
AU  - Tadros, R.*
AU  - Muggenthaler, M.*
AU  - Raju, H.*
AU  - Denjoy, I.*
AU  - Schott, J.J.*
AU  - Gourraud, J.B.*
AU  - Skoric-Milosavljevic, D.*
AU  - Nannenberg, E.A.*
AU  - Redon, R.*
AU  - Papadakis, M.*
AU  - Kyndt, F.*
AU  - Dagradi, F.*
AU  - Castelletti, S.*
AU  - Torchio, M.*
AU  - Meitinger, T.
AU  - Lichtner, P.
AU  - Ishikawa, T.*
AU  - Wilde, A.A.M.*
AU  - Takahashi, K.*
AU  - Sharma, S.*
AU  - Roden, D.M.*
AU  - Borggrefe, M.M.*
AU  - McKeown, P.P.*
AU  - Shimizu, W.*
AU  - Horie, M.*
AU  - Makita, N.*
AU  - Aiba, T.*
AU  - Ackerman, M.J.*
AU  - Schwartz, P.J.*
AU  - Probst, V.*
AU  - Bezzina, C.R.*
AU  - Behr, E.R.*
C1  - 60859
C2  - 49649
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
SP  - 599-608
TI  - Scn5a mutation type and a genetic risk score associate variably with brugada syndrome phenotype in scn5a families.
JO  - Circ. Genom. Precis. Med.
VL  - 13
IS  - 6
PB  - Lippincott Williams & Wilkins
PY  - 2020
SN  - 2574-8300
ER  - 

TY  - JOUR
AB  - BACKGROUND: QT interval, measured through a standard ECG, captures the time it takes for the cardiac ventricles to depolarize and repolarize. JT interval is the component of the QT interval that reflects ventricular repolarization alone. Prolonged QT interval has been linked to higher risk of sudden cardiac arrest. METHODS AND RESULTS: We performed an ExomeChip-wide analysis for both QT and JT intervals, including 209 449 variants, both common and rare, in 17 341 genes from the Illumina Infinium HumanExome BeadChip. We identified 10 loci that modulate QT and JT interval duration that have not been previously reported in the literature using single-variant statistical models in a meta-analysis of 95 626 individuals from 23 cohorts (comprised 83 884 European ancestry individuals, 9610 blacks, 1382 Hispanics, and 750 Asians). This brings the total number of ventricular repolarization associated loci to 45. In addition, our approach of using coding variants has highlighted the role of 17 specific genes for involvement in ventricular repolarization, 7 of which are in novel loci. CONCLUSIONS: Our analyses show a role for myocyte internal structure and interconnections in modulating QT interval duration, adding to previous known roles of potassium, sodium, and calcium ion regulation, as well as autonomic control. We anticipate that these discoveries will open new paths to the goal of making novel remedies for the prevention of lethal ventricular arrhythmias and sudden cardiac arrest.
AU  - Bihlmeyer, N.A.*
AU  - Brody, J.A.*
AU  - Smith, A.V.*
AU  - Warren, H.R.*
AU  - Lin, H.*
AU  - Isaacs, A.*
AU  - Liu, C.*
AU  - Marten, J.*
AU  - Radmanesh, F.*
AU  - Hall, L.M.*
AU  - Grarup, N.*
AU  - Mei, H.*
AU  - Müller-Nurasyid, M.
AU  - Huffman, J.E.*
AU  - Verweij, N.*
AU  - Guo, X.*
AU  - Yao, J.*
AU  - Li-Gao, R.*
AU  - van den Berg, M.*
AU  - Weiss, S.*
AU  - Prins, B.P.*
AU  - van Setten, J.*
AU  - Haessler, J.*
AU  - Lyytikainen, L.*
AU  - Li, M.*
AU  - Alonso, A.*
AU  - Soliman, E.Z.*
AU  - Bis, J.C.*
AU  - Austin, T.*
AU  - Chen, Y.I.*
AU  - Psaty, B.M.*
AU  - Harrris, T.B.*
AU  - Launer, L.J.*
AU  - Padmanabhan, S.*
AU  - Dominiczak, A.*
AU  - Huang, P.L.*
AU  - Xie, Z.*
AU  - Ellinor, P.T.*
AU  - Kors, J.A.*
AU  - Campbell, A.*
AU  - Murray, A.D.*
AU  - Nelson, C.P.*
AU  - Tobin, M.D.*
AU  - Bork-Jensen, J.*
AU  - Hansen, T.*
AU  - Pedersen, O.*
AU  - Linneberg, A.*
AU  - Sinner, M.F.*
AU  - Peters, A.
AU  - Waldenberger, M.
AU  - Meitinger, T.
AU  - Perz, S.
AU  - Kolcic, I.*
AU  - Rudan, I.*
AU  - de Boer, R.A.*
AU  - van der Meer, P.*
AU  - Lin, H.J.*
AU  - Taylor, K.D.*
AU  - de Mutsert, R.*
AU  - Trompet, S.*
AU  - Jukema, J.W.*
AU  - Maan, A.C.*
AU  - Stricker, B.H.C.*
AU  - Rivadeneira, F.*
AU  - Uitterlinden, A.*
AU  - Völker, U.*
AU  - Homuth, G.*
AU  - Völzke, H.*
AU  - Felix, S.B.*
AU  - Mangino, M.*
AU  - Spector, T.D.*
AU  - Bots, M.L.*
AU  - Perez, M.L.*
AU  - Raitakari, O.T.*
AU  - Kähönen, M.*
AU  - Mononen, N.*
AU  - Gudnason, V.*
AU  - Munroe, P.B.*
AU  - Lubitz, S.A.*
AU  - van Duijn, C.M.*
AU  - Newton-Cheh, C.H.*
AU  - Hayward, C.*
AU  - Rosand, J.*
AU  - Samani, N.J.*
AU  - Kanters, J.K.*
AU  - Wilson, J.G.*
AU  - Kääb, S.*
AU  - Polasek, O.*
AU  - van der Harst, P.*
AU  - Heckbert, S.R.*
AU  - Rotter, J.I.*
AU  - Mook-Kanamori, D.O.*
AU  - Eij-Gelsheim, M.*
AU  - Dörr, M.*
AU  - Jamshidi, Y.*
AU  - Asselbergs, F.W.*
AU  - Kooperberg, C.*
AU  - Lehtimäki, T.*
AU  - Arking, D.E.*
AU  - Sotoodehnia, N.*
C1  - 53431
C2  - 44734
CY  - Philadelphia
TI  - ExomeChip-wide analysis of 95 626 individuals identifies 10 novel loci associated with QT and JT intervals.
JO  - Circ. Genom. Precis. Med.
VL  - 11
IS  - 1
PB  - Lippincott Williams & Wilkins
PY  - 2018
SN  - 2574-8300
ER  - 

TY  - JOUR
AB  - BACKGROUND: Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequency variants also contribute to PR interval heritability.METHODS: We performed large-scale meta-analyses of the PR interval that included 83 367 participants of European ancestry and 9436 of African ancestry. We examined both common and rare variants associated with the PR interval.RESULTS: We identified 31 genetic loci that were significantly associated with PR interval after Bonferroni correction (P<1.2x10(-6)), including 11 novel loci that have not been reported previously. Many of these loci are involved in heart morphogenesis. In gene-based analysis, we found that multiple rare variants at MYH6 (P=5.9x10(-11)) and SCN5A (P=1.1x10(-7)) were associated with PR interval. SCN5A locus also was implicated in the common variant analysis, whereas MYH6 was a novel locus.CONCLUSIONS: We identified common variants at 11 novel loci and rare variants within 2 gene regions that were significantly associated with PR interval. Our findings provide novel insights to the current understanding of atrioventricular conduction, which is critical for cardiac activity and an important determinant of health.
AU  - Lin, H.*
AU  - van Setten, J.*
AU  - Smith, A.V.*
AU  - Bihlmeyer, N.A.*
AU  - Warren, H.R.*
AU  - Brody, J.A.*
AU  - Radmanesh, F.*
AU  - Hall, L.*
AU  - Grarup, N.*
AU  - Müller-Nurasyid, M.
AU  - Boutin, T.*
AU  - Verweij, N.*
AU  - Lin, H.J.*
AU  - Li-Gao, R.*
AU  - van den Berg, M.E.*
AU  - Marten, J.*
AU  - Weiss, S.*
AU  - Prins, B.P.*
AU  - Haessler, J.*
AU  - Lyytikäinen, L.-P.*
AU  - Mei, H.*
AU  - Harris, T.B.*
AU  - Launer, L.J.*
AU  - Li, M.*
AU  - Alonso, A.*
AU  - Soliman, E.Z.*
AU  - Connell, J.M.*
AU  - Huang, P.L.*
AU  - Weng, L.C.*
AU  - Jameson, H.S.*
AU  - Hucker, W.*
AU  - Hanley, A.*
AU  - Tucker, N.R.*
AU  - Chen, Y.I.*
AU  - Bis, J.C.*
AU  - Rice, K.M.*
AU  - Sitlani, C.M.*
AU  - Kors, J.A.*
AU  - Xie, Z.*
AU  - Wen, C.*
AU  - Magnani, J.W.*
AU  - Nelson, C.P.*
AU  - Kanters, J.K.*
AU  - Sinner, M.F.*
AU  - Strauch, K.
AU  - Peters, A.
AU  - Waldenberger, M.
AU  - Meitinger, T.
AU  - Bork-Jensen, J.*
AU  - Pedersen, O.*
AU  - Linneberg, A.*
AU  - Rudan, I.*
AU  - de Boer, R.A.*
AU  - van der Meer, P.*
AU  - Yao, J.*
AU  - Guo, X.*
AU  - Taylor, K.D.*
AU  - Sotoodehnia, N.*
AU  - Rotter, J.I.*
AU  - Mook-Kanamori, D.O.*
AU  - Trompet, S.*
AU  - Rivadeneira, F.*
AU  - Uitterlinden, A.*
AU  - Eijgelsheim, M.*
AU  - Padmanabhan, S.*
AU  - Smith, B.H.*
AU  - Völzke, H.*
AU  - Felix, S.B.*
AU  - Homuth, G.*
AU  - Völker, U.*
AU  - Mangino, M.*
AU  - Spector, T.D.*
AU  - Bots, M.L.*
AU  - Perez, M.L.*
AU  - Kähönen, M.*
AU  - Raitakari, O.T.*
AU  - Gudnason, V.*
AU  - Arking, D.E.*
AU  - Munroe, P.B.*
AU  - Psaty, B.M.*
AU  - van Duijn, C.M.*
AU  - Benjamin, E.J.*
AU  - Rosand, J.*
AU  - Samani, N.J.*
AU  - Hansen, T.*
AU  - Kääb, S.*
AU  - Polasek, O.*
AU  - van der Harst, P.*
AU  - Heckbert, S.R.*
AU  - Jukema, J.W.*
AU  - Stricker, B.H.*
AU  - Hayward, C.*
AU  - Dörr, M.*
AU  - Jamshidi, Y.*
AU  - Asselbergs, F.W.*
AU  - Kooperberg, C.*
AU  - Lehtimäki, T.*
AU  - Wilson, J.G.*
AU  - Ellinor, P.T.*
AU  - Lubitz, S.A.*
AU  - Isaacs, A.*
C1  - 53510
C2  - 44883
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
TI  - Common and rare coding genetic variation underlying the electrocardiographic PR interval.
JO  - Circ. Genom. Precis. Med.
VL  - 11
IS  - 5
PB  - Lippincott Williams & Wilkins
PY  - 2018
SN  - 2574-8300
ER  -