@article {1198, title = {Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies.}, journal = {Lancet}, volume = {375}, year = {2010}, month = {2010 May 08}, pages = {1634-9}, abstract = {

BACKGROUND: Whether triglyceride-mediated pathways are causally relevant to coronary heart disease is uncertain. We studied a genetic variant that regulates triglyceride concentration to help judge likelihood of causality.

METHODS: We assessed the -1131T>C (rs662799) promoter polymorphism of the apolipoprotein A5 (APOA5) gene in relation to triglyceride concentration, several other risk factors, and risk of coronary heart disease. We compared disease risk for genetically-raised triglyceride concentration (20,842 patients with coronary heart disease, 35,206 controls) with that recorded for equivalent differences in circulating triglyceride concentration in prospective studies (302 430 participants with no history of cardiovascular disease; 12,785 incident cases of coronary heart disease during 2.79 million person-years at risk). We analysed -1131T>C in 1795 people without a history of cardiovascular disease who had information about lipoprotein concentration and diameter obtained by nuclear magnetic resonance spectroscopy.

FINDINGS: The minor allele frequency of -1131T>C was 8\% (95\% CI 7-9). -1131T>C was not significantly associated with several non-lipid risk factors or LDL cholesterol, and it was modestly associated with lower HDL cholesterol (mean difference per C allele 3.5\% [95\% CI 2.6-4.6]; 0.053 mmol/L [0.039-0.068]), lower apolipoprotein AI (1.3\% [0.3-2.3]; 0.023 g/L [0.005-0.041]), and higher apolipoprotein B (3.2\% [1.3-5.1]; 0.027 g/L [0.011-0.043]). By contrast, for every C allele inherited, mean triglyceride concentration was 16.0\% (95\% CI 12.9-18.7), or 0.25 mmol/L (0.20-0.29), higher (p=4.4x10(-24)). The odds ratio for coronary heart disease was 1.18 (95\% CI 1.11-1.26; p=2.6x10(-7)) per C allele, which was concordant with the hazard ratio of 1.10 (95\% CI 1.08-1.12) per 16\% higher triglyceride concentration recorded in prospective studies. -1131T>C was significantly associated with higher VLDL particle concentration (mean difference per C allele 12.2 nmol/L [95\% CI 7.7-16.7]; p=9.3x10(-8)) and smaller HDL particle size (0.14 nm [0.08-0.20]; p=7.0x10(-5)), factors that could mediate the effects of triglyceride.

INTERPRETATION: These data are consistent with a causal association between triglyceride-mediated pathways and coronary heart disease.

FUNDING: British Heart Foundation, UK Medical Research Council, Novartis.

}, keywords = {Apolipoprotein A-V, Apolipoproteins, Apolipoproteins A, Coronary Disease, Gene Frequency, Genotype, Humans, Lipids, Lipoproteins, HDL, Lipoproteins, LDL, Lipoproteins, VLDL, Mendelian Randomization Analysis, Particle Size, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Risk Factors, Triglycerides}, issn = {1474-547X}, doi = {10.1016/S0140-6736(10)60545-4}, author = {Sarwar, Nadeem and Sandhu, Manjinder S and Ricketts, Sally L and Butterworth, Adam S and Di Angelantonio, Emanuele and Boekholdt, S Matthijs and Ouwehand, Willem and Watkins, Hugh and Samani, Nilesh J and Saleheen, Danish and Lawlor, Debbie and Reilly, Muredach P and Hingorani, Aroon D and Talmud, Philippa J and Danesh, John} } @article {6288, title = {Common variants in Mendelian kidney disease genes and their association with renal function.}, journal = {J Am Soc Nephrol}, volume = {24}, year = {2013}, month = {2013 Dec}, pages = {2105-17}, abstract = {

Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5\%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.

}, keywords = {Databases, Genetic, European Continental Ancestry Group, Gene Frequency, Genetic Variation, Genome-Wide Association Study, Humans, Kidney, Mendelian Randomization Analysis, Phenotype, Polymorphism, Single Nucleotide, Renal Insufficiency, Chronic}, issn = {1533-3450}, doi = {10.1681/ASN.2012100983}, author = {Parsa, Afshin and Fuchsberger, Christian and K{\"o}ttgen, Anna and O{\textquoteright}Seaghdha, Conall M and Pattaro, Cristian and de Andrade, Mariza and Chasman, Daniel I and Teumer, Alexander and Endlich, Karlhans and Olden, Matthias and Chen, Ming-Huei and Tin, Adrienne and Kim, Young J and Taliun, Daniel and Li, Man and Feitosa, Mary and Gorski, Mathias and Yang, Qiong and Hundertmark, Claudia and Foster, Meredith C and Glazer, Nicole and Isaacs, Aaron and Rao, Madhumathi and Smith, Albert V and O{\textquoteright}Connell, Jeffrey R and Struchalin, Maksim and Tanaka, Toshiko and Li, Guo and Hwang, Shih-Jen and Atkinson, Elizabeth J and Lohman, Kurt and Cornelis, Marilyn C and Johansson, Asa and T{\"o}njes, Anke and Dehghan, Abbas and Couraki, Vincent and Holliday, Elizabeth G and Sorice, Rossella and Kutalik, Zolt{\'a}n and Lehtim{\"a}ki, Terho and Esko, T{\~o}nu and Deshmukh, Harshal and Ulivi, Sheila and Chu, Audrey Y and Murgia, Federico and Trompet, Stella and Imboden, Medea and Kollerits, Barbara and Pistis, Giorgio and Harris, Tamara B and Launer, Lenore J and Aspelund, Thor and Eiriksdottir, Gudny and Mitchell, Braxton D and Boerwinkle, Eric and Schmidt, Helena and Hofer, Edith and Hu, Frank and Demirkan, Ayse and Oostra, Ben A and Turner, Stephen T and Ding, Jingzhong and Andrews, Jeanette S and Freedman, Barry I and Giulianini, Franco and Koenig, Wolfgang and Illig, Thomas and D{\"o}ring, Angela and Wichmann, H-Erich and Zgaga, Lina and Zemunik, Tatijana and Boban, Mladen and Minelli, Cosetta and Wheeler, Heather E and Igl, Wilmar and Zaboli, Ghazal and Wild, Sarah H and Wright, Alan F and Campbell, Harry and Ellinghaus, David and N{\"o}thlings, Ute and Jacobs, Gunnar and Biffar, Reiner and Ernst, Florian and Homuth, Georg and Kroemer, Heyo K and Nauck, Matthias and Stracke, Sylvia and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Kovacs, Peter and Stumvoll, Michael and M{\"a}gi, Reedik and Hofman, Albert and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and Aulchenko, Yurii S and Polasek, Ozren and Hastie, Nick and Vitart, Veronique and Helmer, Catherine and Wang, Jie Jin and Stengel, B{\'e}n{\'e}dicte and Ruggiero, Daniela and Bergmann, Sven and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and Nikopensius, Tiit and Province, Michael and Colhoun, Helen and Doney, Alex and Robino, Antonietta and Kr{\"a}mer, Bernhard K and Portas, Laura and Ford, Ian and Buckley, Brendan M and Adam, Martin and Thun, Gian-Andri and Paulweber, Bernhard and Haun, Margot and Sala, Cinzia and Mitchell, Paul and Ciullo, Marina and Vollenweider, Peter and Raitakari, Olli and Metspalu, Andres and Palmer, Colin and Gasparini, Paolo and Pirastu, Mario and Jukema, J Wouter and Probst-Hensch, Nicole M and Kronenberg, Florian and Toniolo, Daniela and Gudnason, Vilmundur and Shuldiner, Alan R and Coresh, Josef and Schmidt, Reinhold and Ferrucci, Luigi and van Duijn, Cornelia M and Borecki, Ingrid and Kardia, Sharon L R and Liu, Yongmei and Curhan, Gary C and Rudan, Igor and Gyllensten, Ulf and Wilson, James F and Franke, Andre and Pramstaller, Peter P and Rettig, Rainer and Prokopenko, Inga and Witteman, Jacqueline and Hayward, Caroline and Ridker, Paul M and Bochud, Murielle and Heid, Iris M and Siscovick, David S and Fox, Caroline S and Kao, W Linda and B{\"o}ger, Carsten A} } @article {6569, title = {Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data.}, journal = {BMJ}, volume = {349}, year = {2014}, month = {2014 Jul 10}, pages = {g4164}, abstract = {

OBJECTIVE: To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease.

DESIGN: Mendelian randomisation meta-analysis of 56 epidemiological studies.

PARTICIPANTS: 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers.

MAIN OUTCOME MEASURES: Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption.

RESULTS: Carriers of the A-allele of ADH1B rs1229984 consumed 17.2\% fewer units of alcohol per week (95\% confidence interval 15.6\% to 18.9\%), had a lower prevalence of binge drinking (odds ratio 0.78 (95\% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2\% (-7.8 to -2.4\%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)).

CONCLUSIONS: Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health.

}, keywords = {Adult, Aged, Alcohol Dehydrogenase, Alcohol Drinking, Biomarkers, Coronary Disease, Female, Genetic Markers, Genotype, Humans, Male, Mendelian Randomization Analysis, Middle Aged, Models, Statistical, Polymorphism, Single Nucleotide, Stroke}, issn = {1756-1833}, doi = {10.1136/bmj.g4164}, author = {Holmes, Michael V and Dale, Caroline E and Zuccolo, Luisa and Silverwood, Richard J and Guo, Yiran and Ye, Zheng and Prieto-Merino, David and Dehghan, Abbas and Trompet, Stella and Wong, Andrew and Cavadino, Alana and Drogan, Dagmar and Padmanabhan, Sandosh and Li, Shanshan and Yesupriya, Ajay and Leusink, Maarten and Sundstr{\"o}m, Johan and Hubacek, Jaroslav A and Pikhart, Hynek and Swerdlow, Daniel I and Panayiotou, Andrie G and Borinskaya, Svetlana A and Finan, Chris and Shah, Sonia and Kuchenbaecker, Karoline B and Shah, Tina and Engmann, Jorgen and Folkersen, Lasse and Eriksson, Per and Ricceri, Fulvio and Melander, Olle and Sacerdote, Carlotta and Gamble, Dale M and Rayaprolu, Sruti and Ross, Owen A and McLachlan, Stela and Vikhireva, Olga and Sluijs, Ivonne and Scott, Robert A and Adamkova, Vera and Flicker, Leon and Bockxmeer, Frank M van and Power, Christine and Marques-Vidal, Pedro and Meade, Tom and Marmot, Michael G and Ferro, Jose M and Paulos-Pinheiro, Sofia and Humphries, Steve E and Talmud, Philippa J and Mateo Leach, Irene and Verweij, Niek and Linneberg, Allan and Skaaby, Tea and Doevendans, Pieter A and Cramer, Maarten J and van der Harst, Pim and Klungel, Olaf H and Dowling, Nicole F and Dominiczak, Anna F and Kumari, Meena and Nicolaides, Andrew N and Weikert, Cornelia and Boeing, Heiner and Ebrahim, Shah and Gaunt, Tom R and Price, Jackie F and Lannfelt, Lars and Peasey, Anne and Kubinova, Ruzena and Pajak, Andrzej and Malyutina, Sofia and Voevoda, Mikhail I and Tamosiunas, Abdonas and Maitland-van der Zee, Anke H and Norman, Paul E and Hankey, Graeme J and Bergmann, Manuela M and Hofman, Albert and Franco, Oscar H and Cooper, Jackie and Palmen, Jutta and Spiering, Wilko and de Jong, Pim A and Kuh, Diana and Hardy, Rebecca and Uitterlinden, Andr{\'e} G and Ikram, M Arfan and Ford, Ian and Hypp{\"o}nen, Elina and Almeida, Osvaldo P and Wareham, Nicholas J and Khaw, Kay-Tee and Hamsten, Anders and Husemoen, Lise Lotte N and Tj{\o}nneland, Anne and Tolstrup, Janne S and Rimm, Eric and Beulens, Joline W J and Verschuren, W M Monique and Onland-Moret, N Charlotte and Hofker, Marten H and Wannamethee, S Goya and Whincup, Peter H and Morris, Richard and Vicente, Astrid M and Watkins, Hugh and Farrall, Martin and Jukema, J Wouter and Meschia, James and Cupples, L Adrienne and Sharp, Stephen J and Fornage, Myriam and Kooperberg, Charles and LaCroix, Andrea Z and Dai, James Y and Lanktree, Matthew B and Siscovick, David S and Jorgenson, Eric and Spring, Bonnie and Coresh, Josef and Li, Yun R and Buxbaum, Sarah G and Schreiner, Pamela J and Ellison, R Curtis and Tsai, Michael Y and Patel, Sanjay R and Redline, Susan and Johnson, Andrew D and Hoogeveen, Ron C and Hakonarson, Hakon and Rotter, Jerome I and Boerwinkle, Eric and de Bakker, Paul I W and Kivimaki, Mika and Asselbergs, Folkert W and Sattar, Naveed and Lawlor, Debbie A and Whittaker, John and Davey Smith, George and Mukamal, Kenneth and Psaty, Bruce M and Wilson, James G and Lange, Leslie A and Hamidovic, Ajna and Hingorani, Aroon D and Nordestgaard, B{\o}rge G and Bobak, Martin and Leon, David A and Langenberg, Claudia and Palmer, Tom M and Reiner, Alex P and Keating, Brendan J and Dudbridge, Frank and Casas, Juan P} } @article {6853, title = {Fetuin-A and risk of coronary heart disease: A Mendelian randomization analysis and a pooled analysis of AHSG genetic variants in 7 prospective studies.}, journal = {Atherosclerosis}, volume = {243}, year = {2015}, month = {2015 Nov}, pages = {44-52}, abstract = {

BACKGROUND AND AIMS: Fetuin-A has a plausible role in the inhibition of arterial calcification, but its association with risk of coronary heart disease (CHD) in the general population is unclear. We used two common genetic variants in the fetuin-A gene (AHSG) that are strongly associated with circulating fetuin-A levels to investigate the associations with risk of CHD and subclinical cardiovascular measures (intima-media thickness, ankle-arm index, and coronary artery calcification).

METHODS: Genetic variation and fetuin-A levels were assessed in 3299 community-living individuals (2733 Caucasians and 566 African Americans) 65 years of age or older, free of previous cardiovascular disease, who participated in the Cardiovascular Health Study (CHS) in 1992-1993.

RESULTS: Among Caucasians, both rs2248690 and rs4917 were associated with 12\% lower fetuin-A concentrations per minor allele (P~<~0.0001). The hazard ratios (HRs) per minor allele for incident CHD were 1.12 (95\% CI: 1.00-1.26) for rs2248690 and 1.02 (0.91-1.14) for rs4917. Using both genotypes as an instrumental variable for measured fetuin-A, the HRs for one standard deviation increase in genetically determined fetuin-A levels on CHD risk were 0.84 (95\% CI: 0.70-1.00) for rs2248690 and 0.97 (95\% CI: 0.82-1.14) for rs4917, respectively. However, in CHS neither of the genotypes were associated with subclinical cardiovascular measures and when CHS data were meta-analyzed with data from six other prospective studies (totaling 26,702 Caucasian participants and 3295 CHD cases), the meta-analyzed HRs for incident CHD were 1.12 (0.93-1.34) and 1.06 (0.93-1.20) for rs2248690 and rs4917, respectively (p heterogeneity 0.005 and 0.0048).

CONCLUSION: Common variants in the AHSG gene are strongly associated with fetuin-A levels, but their concurrent association with CHD risk in current prospective studies is inconsistent. Further investigation in studies with measured fetuin-A and AHSG variants is needed to clarify the potential causal association of fetuin-A with CHD risk.

}, keywords = {Aged, Aged, 80 and over, alpha-2-HS-Glycoprotein, Carotid Intima-Media Thickness, Coronary Vessels, Female, Genetic Variation, Genotype, Heart Diseases, Humans, Insulin Resistance, Longitudinal Studies, Male, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, Prospective Studies, Risk Factors, Vascular Calcification}, issn = {1879-1484}, doi = {10.1016/j.atherosclerosis.2015.08.031}, author = {Laugsand, Lars E and Ix, Joachim H and Bartz, Traci M and Djouss{\'e}, Luc and Kizer, Jorge R and Tracy, Russell P and Dehghan, Abbas and Rexrode, Kathryn and Lopez, Oscar L and Rimm, Eric B and Siscovick, David S and O{\textquoteright}Donnell, Christopher J and Newman, Anne and Mukamal, Kenneth J and Jensen, Majken K} } @article {6568, title = {Mendelian randomization of blood lipids for coronary heart disease.}, journal = {Eur Heart J}, volume = {36}, year = {2015}, month = {2015 Mar 01}, pages = {539-50}, abstract = {

AIMS: To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization.

METHODS AND RESULTS: We developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a prior meta-analysis (threshold P < 2 {\texttimes} 10(-6)); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P <= 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestricted allele score (48 SNPs) was associated with CHD (OR: 0.53; 95\% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95\% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95\% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95\% CI: 1.24, 2.11 and 1.61; 95\% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95\% CI: 0.59, 1.75).

CONCLUSION: The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.

}, keywords = {Case-Control Studies, Cholesterol, HDL, Coronary Artery Disease, Female, Gene Frequency, Genotype, Genotyping Techniques, Humans, Male, Mendelian Randomization Analysis, Middle Aged, Polymorphism, Single Nucleotide, Risk Assessment, Triglycerides}, issn = {1522-9645}, doi = {10.1093/eurheartj/eht571}, author = {Holmes, Michael V and Asselbergs, Folkert W and Palmer, Tom M and Drenos, Fotios and Lanktree, Matthew B and Nelson, Christopher P and Dale, Caroline E and Padmanabhan, Sandosh and Finan, Chris and Swerdlow, Daniel I and Tragante, Vinicius and van Iperen, Erik P A and Sivapalaratnam, Suthesh and Shah, Sonia and Elbers, Clara C and Shah, Tina and Engmann, Jorgen and Giambartolomei, Claudia and White, Jon and Zabaneh, Delilah and Sofat, Reecha and McLachlan, Stela and Doevendans, Pieter A and Balmforth, Anthony J and Hall, Alistair S and North, Kari E and Almoguera, Berta and Hoogeveen, Ron C and Cushman, Mary and Fornage, Myriam and Patel, Sanjay R and Redline, Susan and Siscovick, David S and Tsai, Michael Y and Karczewski, Konrad J and Hofker, Marten H and Verschuren, W Monique and Bots, Michiel L and van der Schouw, Yvonne T and Melander, Olle and Dominiczak, Anna F and Morris, Richard and Ben-Shlomo, Yoav and Price, Jackie and Kumari, Meena and Baumert, Jens and Peters, Annette and Thorand, Barbara and Koenig, Wolfgang and Gaunt, Tom R and Humphries, Steve E and Clarke, Robert and Watkins, Hugh and Farrall, Martin and Wilson, James G and Rich, Stephen S and de Bakker, Paul I W and Lange, Leslie A and Davey Smith, George and Reiner, Alex P and Talmud, Philippa J and Kivimaki, Mika and Lawlor, Debbie A and Dudbridge, Frank and Samani, Nilesh J and Keating, Brendan J and Hingorani, Aroon D and Casas, Juan P} } @article {7777, title = {Assessing the causal relationship between obesity and venous thromboembolism through a Mendelian Randomization study.}, journal = {Hum Genet}, volume = {136}, year = {2017}, month = {2017 07}, pages = {897-902}, abstract = {

Observational studies have shown an association between obesity and venous thromboembolism (VTE) but it is not known if observed associations are causal, due to reverse causation or confounding bias. We conducted a Mendelian Randomization study of body mass index (BMI) and VTE. We identified 95 single nucleotide polymorphisms (SNPs) that have been previously associated with BMI and assessed the association between genetically predicted high BMI and VTE leveraging data from a previously conducted GWAS within the INVENT consortium comprising a total of 7507 VTE cases and 52,632 controls of European ancestry. Five BMI SNPs were associated with VTE at P~<~0.05, with the strongest association seen for the FTO SNP rs1558902 (OR 1.07, 95\% CI 1.02-1.12, P~=~0.005). In addition, we observed a significant association between genetically predicted BMI and VTE (OR~=~1.59, 95\% CI 1.30-1.93 per standard deviation increase in BMI, P~=~5.8~{\texttimes}~10). Our study provides evidence for a causal relationship between high BMI and risk of VTE. Reducing obesity levels will likely result in lower incidence in VTE.

}, keywords = {Adult, Body Mass Index, Case-Control Studies, European Continental Ancestry Group, Female, Genome-Wide Association Study, Humans, Incidence, Logistic Models, Male, Mendelian Randomization Analysis, Obesity, Polymorphism, Single Nucleotide, Proportional Hazards Models, Venous Thromboembolism}, issn = {1432-1203}, doi = {10.1007/s00439-017-1811-x}, author = {Lindstr{\"o}m, Sara and Germain, Marine and Crous-Bou, Marta and Smith, Erin N and Morange, Pierre-Emmanuel and van Hylckama Vlieg, Astrid and de Haan, Hugoline G and Chasman, Daniel and Ridker, Paul and Brody, Jennifer and de Andrade, Mariza and Heit, John A and Tang, Weihong and DeVivo, Immaculata and Grodstein, Francine and Smith, Nicholas L and Tregouet, David and Kabrhel, Christopher} } @article {7594, title = {Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study.}, journal = {JAMA Oncol}, volume = {3}, year = {2017}, month = {2017 May 01}, pages = {636-651}, abstract = {

Importance: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation.

Objective: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases.

Data Sources: Genomewide association studies (GWAS) published up to January 15, 2015.

Study Selection: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available.

Data Extraction and Synthesis: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population.

Main Outcomes and Measures: Odds ratios (ORs) and 95\% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation.

Results: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95\% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95\% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95\% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95\% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95\% CI, 0.05-0.15]).

Conclusions and Relevance: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

}, keywords = {Adult, Aged, Aged, 80 and over, Cardiovascular Diseases, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Germ-Line Mutation, Humans, Male, Mendelian Randomization Analysis, Middle Aged, Neoplasms, Polymorphism, Single Nucleotide, Risk Assessment, Telomere, Telomere Homeostasis}, issn = {2374-2445}, doi = {10.1001/jamaoncol.2016.5945}, author = {Haycock, Philip C and Burgess, Stephen and Nounu, Aayah and Zheng, Jie and Okoli, George N and Bowden, Jack and Wade, Kaitlin Hazel and Timpson, Nicholas J and Evans, David M and Willeit, Peter and Aviv, Abraham and Gaunt, Tom R and Hemani, Gibran and Mangino, Massimo and Ellis, Hayley Patricia and Kurian, Kathreena M and Pooley, Karen A and Eeles, Rosalind A and Lee, Jeffrey E and Fang, Shenying and Chen, Wei V and Law, Matthew H and Bowdler, Lisa M and Iles, Mark M and Yang, Qiong and Worrall, Bradford B and Markus, Hugh Stephen and Hung, Rayjean J and Amos, Chris I and Spurdle, Amanda B and Thompson, Deborah J and O{\textquoteright}Mara, Tracy A and Wolpin, Brian and Amundadottir, Laufey and Stolzenberg-Solomon, Rachael and Trichopoulou, Antonia and Onland-Moret, N Charlotte and Lund, Eiliv and Duell, Eric J and Canzian, Federico and Severi, Gianluca and Overvad, Kim and Gunter, Marc J and Tumino, Rosario and Svenson, Ulrika and van Rij, Andre and Baas, Annette F and Bown, Matthew J and Samani, Nilesh J and van t{\textquoteright}Hof, Femke N G and Tromp, Gerard and Jones, Gregory T and Kuivaniemi, Helena and Elmore, James R and Johansson, Mattias and Mckay, James and Scelo, Ghislaine and Carreras-Torres, Robert and Gaborieau, Valerie and Brennan, Paul and Bracci, Paige M and Neale, Rachel E and Olson, Sara H and Gallinger, Steven and Li, Donghui and Petersen, Gloria M and Risch, Harvey A and Klein, Alison P and Han, Jiali and Abnet, Christian C and Freedman, Neal D and Taylor, Philip R and Maris, John M and Aben, Katja K and Kiemeney, Lambertus A and Vermeulen, Sita H and Wiencke, John K and Walsh, Kyle M and Wrensch, Margaret and Rice, Terri and Turnbull, Clare and Litchfield, Kevin and Paternoster, Lavinia and Standl, Marie and Abecasis, Goncalo R and SanGiovanni, John Paul and Li, Yong and Mijatovic, Vladan and Sapkota, Yadav and Low, Siew-Kee and Zondervan, Krina T and Montgomery, Grant W and Nyholt, Dale R and van Heel, David A and Hunt, Karen and Arking, Dan E and Ashar, Foram N and Sotoodehnia, Nona and Woo, Daniel and Rosand, Jonathan and Comeau, Mary E and Brown, W Mark and Silverman, Edwin K and Hokanson, John E and Cho, Michael H and Hui, Jennie and Ferreira, Manuel A and Thompson, Philip J and Morrison, Alanna C and Felix, Janine F and Smith, Nicholas L and Christiano, Angela M and Petukhova, Lynn and Betz, Regina C and Fan, Xing and Zhang, Xuejun and Zhu, Caihong and Langefeld, Carl D and Thompson, Susan D and Wang, Feijie and Lin, Xu and Schwartz, David A and Fingerlin, Tasha and Rotter, Jerome I and Cotch, Mary Frances and Jensen, Richard A and Munz, Matthias and Dommisch, Henrik and Schaefer, Arne S and Han, Fang and Ollila, Hanna M and Hillary, Ryan P and Albagha, Omar and Ralston, Stuart H and Zeng, Chenjie and Zheng, Wei and Shu, Xiao-Ou and Reis, Andre and Uebe, Steffen and H{\"u}ffmeier, Ulrike and Kawamura, Yoshiya and Otowa, Takeshi and Sasaki, Tsukasa and Hibberd, Martin Lloyd and Davila, Sonia and Xie, Gang and Siminovitch, Katherine and Bei, Jin-Xin and Zeng, Yi-Xin and F{\"o}rsti, Asta and Chen, Bowang and Landi, Stefano and Franke, Andre and Fischer, Annegret and Ellinghaus, David and Flores, Carlos and Noth, Imre and Ma, Shwu-Fan and Foo, Jia Nee and Liu, Jianjun and Kim, Jong-Won and Cox, David G and Delattre, Olivier and Mirabeau, Olivier and Skibola, Christine F and Tang, Clara S and Garcia-Barcelo, Merce and Chang, Kai-Ping and Su, Wen-Hui and Chang, Yu-Sun and Martin, Nicholas G and Gordon, Scott and Wade, Tracey D and Lee, Chaeyoung and Kubo, Michiaki and Cha, Pei-Chieng and Nakamura, Yusuke and Levy, Daniel and Kimura, Masayuki and Hwang, Shih-Jen and Hunt, Steven and Spector, Tim and Soranzo, Nicole and Manichaikul, Ani W and Barr, R Graham and Kahali, Bratati and Speliotes, Elizabeth and Yerges-Armstrong, Laura M and Cheng, Ching-Yu and Jonas, Jost B and Wong, Tien Yin and Fogh, Isabella and Lin, Kuang and Powell, John F and Rice, Kenneth and Relton, Caroline L and Martin, Richard M and Davey Smith, George} } @article {7452, title = {Dairy consumption, systolic blood pressure, and risk of hypertension: Mendelian randomization study.}, journal = {BMJ}, volume = {356}, year = {2017}, month = {2017 03 16}, pages = {j1000}, abstract = {

Objective~To examine whether previous observed inverse associations of dairy intake with systolic blood pressure and risk of hypertension were causal.Design~Mendelian randomization study using the single nucleotide polymorphism rs4988235 related to lactase persistence as an instrumental variable.Setting~CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium.Participants~Data from 22 studies with 171 213 participants, and an additional 10 published prospective studies with 26 119 participants included in the observational analysis.Main outcome measures~The instrumental variable estimation was conducted using the ratio of coefficients approach. Using meta-analysis, an additional eight published randomized clinical trials on the association of dairy consumption with systolic blood pressure were summarized.Results~Compared with the CC genotype (CC is associated with complete lactase deficiency), the CT/TT genotype (TT is associated with lactose persistence, and CT is associated with certain lactase deficiency) of LCT-13910 (lactase persistence gene) rs4988235 was associated with higher dairy consumption (0.23 (about 55 g/day), 95\% confidence interval 0.17 to 0.29) serving/day; P<0.001) and was not associated with systolic blood pressure (0.31, 95\% confidence interval -0.05 to 0.68 mm Hg; P=0.09) or risk of hypertension (odds ratio 1.01, 95\% confidence interval 0.97 to 1.05; P=0.27). Using LCT-13910 rs4988235 as the instrumental variable, genetically determined dairy consumption was not associated with systolic blood pressure (β=1.35, 95\% confidence interval -0.28 to 2.97 mm Hg for each serving/day) or risk of hypertension (odds ratio 1.04, 0.88 to 1.24). Moreover, meta-analysis of the published clinical trials showed that higher dairy intake has no significant effect on change in systolic blood pressure for interventions over one month to 12 months (intervention compared with control groups: β=-0.21, 95\% confidence interval -0.98 to 0.57 mm Hg). In observational analysis, each serving/day increase in dairy consumption was associated with -0.11 (95\% confidence interval -0.20 to -0.02 mm Hg; P=0.02) lower systolic blood pressure but not risk of hypertension (odds ratio 0.98, 0.97 to 1.00; P=0.11).Conclusion~The weak inverse association between dairy intake and systolic blood pressure in observational studies was not supported by a comprehensive instrumental variable analysis and systematic review of existing clinical trials.

}, keywords = {Blood Pressure, Dairy Products, Feeding Behavior, Genetic Predisposition to Disease, Humans, Hypertension, Lactase, Mendelian Randomization Analysis, Observational Studies as Topic, Polymorphism, Single Nucleotide, Randomized Controlled Trials as Topic}, issn = {1756-1833}, doi = {10.1136/bmj.j1000}, author = {Ding, Ming and Huang, Tao and Bergholdt, Helle Km and Nordestgaard, B{\o}rge G and Ellervik, Christina and Qi, Lu} } @article {7583, title = {DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation.}, journal = {Am J Hum Genet}, volume = {101}, year = {2017}, month = {2017 Dec 07}, pages = {888-902}, abstract = {

Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p < 1.0~{\texttimes} 10-7; replication: N = 7,182, p~<~1.6~{\texttimes} 10-3). The replicated methylation sites are heritable (h2 > 30\%) and independent of known BP genetic variants, explaining an additional 1.4\% and 2.0\% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.

}, keywords = {Aged, Blood Pressure, CpG Islands, Cross-Sectional Studies, DNA Methylation, Epigenesis, Genetic, Genetic Variation, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Middle Aged, Nerve Tissue Proteins, Quantitative Trait Loci, Tetraspanins}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.09.028}, author = {Richard, Melissa A and Huan, Tianxiao and Ligthart, Symen and Gondalia, Rahul and Jhun, Min A and Brody, Jennifer A and Irvin, Marguerite R and Marioni, Riccardo and Shen, Jincheng and Tsai, Pei-Chien and Montasser, May E and Jia, Yucheng and Syme, Catriona and Salfati, Elias L and Boerwinkle, Eric and Guan, Weihua and Mosley, Thomas H and Bressler, Jan and Morrison, Alanna C and Liu, Chunyu and Mendelson, Michael M and Uitterlinden, Andr{\'e} G and van Meurs, Joyce B and Franco, Oscar H and Zhang, Guosheng and Li, Yun and Stewart, James D and Bis, Joshua C and Psaty, Bruce M and Chen, Yii-Der Ida and Kardia, Sharon L R and Zhao, Wei and Turner, Stephen T and Absher, Devin and Aslibekyan, Stella and Starr, John M and McRae, Allan F and Hou, Lifang and Just, Allan C and Schwartz, Joel D and Vokonas, Pantel S and Menni, Cristina and Spector, Tim D and Shuldiner, Alan and Damcott, Coleen M and Rotter, Jerome I and Palmas, Walter and Liu, Yongmei and Paus, Tom{\'a}{\v s} and Horvath, Steve and O{\textquoteright}Connell, Jeffrey R and Guo, Xiuqing and Pausova, Zdenka and Assimes, Themistocles L and Sotoodehnia, Nona and Smith, Jennifer A and Arnett, Donna K and Deary, Ian J and Baccarelli, Andrea A and Bell, Jordana T and Whitsel, Eric and Dehghan, Abbas and Levy, Daniel and Fornage, Myriam} } @article {7590, title = {Genetically Determined Plasma Lipid Levels and Risk of Diabetic Retinopathy: A Mendelian Randomization Study.}, journal = {Diabetes}, volume = {66}, year = {2017}, month = {2017 12}, pages = {3130-3141}, abstract = {

Results from observational studies examining dyslipidemia as a risk factor for diabetic retinopathy (DR) have been inconsistent. We evaluated the causal relationship between plasma lipids and DR using a Mendelian randomization approach. We pooled genome-wide association studies summary statistics from 18 studies for two DR phenotypes: any DR (N = 2,969 case and 4,096 control subjects) and severe DR (N = 1,277 case and 3,980 control subjects). Previously identified lipid-associated single nucleotide polymorphisms served as instrumental variables. Meta-analysis to combine the Mendelian randomization estimates from different cohorts was conducted. There was no statistically significant change in odds ratios of having any DR or severe DR for any of the lipid fractions in the primary analysis that used single nucleotide polymorphisms that did not have a pleiotropic effect on another lipid fraction. Similarly, there was no significant association in the Caucasian and Chinese subgroup analyses. This study did not show evidence of a causal role of the four lipid fractions on DR. However, the study had limited power to detect odds ratios less than 1.23 per SD in genetically induced increase in plasma lipid levels, thus we cannot exclude that causal relationships with more modest effect sizes exist.

}, keywords = {Aged, Diabetic Retinopathy, Female, Genome-Wide Association Study, Humans, Lipids, Male, Mendelian Randomization Analysis, Middle Aged, Polymorphism, Single Nucleotide, Risk}, issn = {1939-327X}, doi = {10.2337/db17-0398}, author = {Sobrin, Lucia and Chong, Yong He and Fan, Qiao and Gan, Alfred and Stanwyck, Lynn K and Kaidonis, Georgia and Craig, Jamie E and Kim, Jihye and Liao, Wen-Ling and Huang, Yu-Chuen and Lee, Wen-Jane and Hung, Yi-Jen and Guo, Xiuqing and Hai, Yang and Ipp, Eli and Pollack, Samuela and Hancock, Heather and Price, Alkes and Penman, Alan and Mitchell, Paul and Liew, Gerald and Smith, Albert V and Gudnason, Vilmundur and Tan, Gavin and Klein, Barbara E K and Kuo, Jane and Li, Xiaohui and Christiansen, Mark W and Psaty, Bruce M and Sandow, Kevin and Jensen, Richard A and Klein, Ronald and Cotch, Mary Frances and Wang, Jie Jin and Jia, Yucheng and Chen, Ching J and Chen, Yii-Der Ida and Rotter, Jerome I and Tsai, Fuu-Jen and Hanis, Craig L and Burdon, Kathryn P and Wong, Tien Yin and Cheng, Ching-Yu} } @article {7564, title = {Short telomere length is associated with impaired cognitive performance in European ancestry cohorts.}, journal = {Transl Psychiatry}, volume = {7}, year = {2017}, month = {2017 04 18}, pages = {e1100}, abstract = {

The association between telomere length (TL) dynamics on cognitive performance over the life-course is not well understood. This study meta-analyses observational and causal associations between TL and six cognitive traits, with stratifications on APOE genotype, in a Mendelian Randomization (MR) framework. Twelve European cohorts (N=17 052; mean age=59.2{\textpm}8.8 years) provided results for associations between qPCR-measured TL (T/S-ratio scale) and general cognitive function, mini-mental state exam (MMSE), processing speed by digit symbol substitution test (DSST), visuospatial functioning, memory and executive functioning (STROOP). In addition, a genetic risk score (GRS) for TL including seven known genetic variants for TL was calculated, and used in associations with cognitive traits as outcomes in all cohorts. Observational analyses showed that longer telomeres were associated with better scores on DSST (β=0.051 per s.d.-increase of TL; 95\% confidence interval (CI): 0.024, 0.077; P=0.0002), and MMSE (β=0.025; 95\% CI: 0.002, 0.047; P=0.03), and faster STROOP (β=-0.053; 95\% CI: -0.087, -0.018; P=0.003). Effects for DSST were stronger in APOE ɛ4 non-carriers (β=0.081; 95\% CI: 0.045, 0.117; P=1.0 {\texttimes} 10-5), whereas carriers performed better in STROOP (β=-0.074; 95\% CI: -0.140, -0.009; P=0.03). Causal associations were found for STROOP only (β=-0.598 per s.d.-increase of TL; 95\% CI: -1.125, -0.072; P=0.026), with a larger effect in ɛ4-carriers (β=-0.699; 95\% CI: -1.330, -0.069; P=0.03). Two-sample replication analyses using CHARGE summary statistics showed causal effects between TL and general cognitive function and DSST, but not with STROOP. In conclusion, we suggest causal effects from longer TL on better cognitive performance, where APOE ɛ4-carriers might be at differential risk.

}, keywords = {Adult, Aged, Apolipoprotein E4, Cognitive Dysfunction, Cohort Studies, European Continental Ancestry Group, Female, Genetic Carrier Screening, Genotype, Humans, Male, Mendelian Randomization Analysis, Middle Aged, Neuropsychological Tests, Psychometrics, Statistics as Topic, Telomere}, issn = {2158-3188}, doi = {10.1038/tp.2017.73}, author = {H{\"a}gg, S and Zhan, Y and Karlsson, R and Gerritsen, L and Ploner, A and van der Lee, S J and Broer, L and Deelen, J and Marioni, R E and Wong, A and Lundquist, A and Zhu, G and Hansell, N K and Sillanp{\"a}{\"a}, E and Fedko, I O and Amin, N A and Beekman, M and de Craen, A J M and Degerman, S and Harris, S E and Kan, K-J and Martin-Ruiz, C M and Montgomery, G W and Adolfsson, A N and Reynolds, C A and Samani, N J and Suchiman, H E D and Viljanen, A and von Zglinicki, T and Wright, M J and Hottenga, J-J and Boomsma, D I and Rantanen, T and Kaprio, J A and Nyholt, D R and Martin, N G and Nyberg, L and Adolfsson, R and Kuh, D and Starr, J M and Deary, I J and Slagboom, P E and van Duijn, C M and Codd, V and Pedersen, N L} } @article {8046, title = {No causal effects of serum urate levels on the risk of chronic kidney disease: A Mendelian randomization study.}, journal = {PLoS Med}, volume = {16}, year = {2019}, month = {2019 01}, pages = {e1002725}, abstract = {

BACKGROUND: Studies have shown strong positive associations between serum urate (SU) levels and chronic kidney disease (CKD) risk; however, whether the relation is causal remains uncertain. We evaluate whether genetic data are consistent with a causal impact of SU level on the risk of CKD and estimated glomerular filtration rate (eGFR).

METHODS AND FINDINGS: We used Mendelian randomization (MR) methods to evaluate the presence of a causal effect. We used aggregated genome-wide association data (N = 110,347 for SU, N = 69,374 for gout, N = 133,413 for eGFR, N = 117,165 for CKD), electronic-medical-record-linked UK Biobank data (N = 335,212), and population-based cohorts (N = 13,425), all in individuals of European ancestry, for SU levels and CKD. Our MR analysis showed that SU has a causal effect on neither eGFR level nor CKD risk across all MR analyses (all P > 0.05). These null associations contrasted with our epidemiological association findings from the 4 population-based cohorts (change in eGFR level per 1-mg/dl [59.48 μmol/l] increase in SU: -1.99 ml/min/1.73 m2; 95\% CI -2.86 to -1.11; P = 8.08 {\texttimes} 10(-6); odds ratio [OR] for CKD: 1.48; 95\% CI 1.32 to 1.65; P = 1.52 {\texttimes} 10(-11)). In contrast, the same MR approaches showed that SU has a causal effect on the risk of gout (OR estimates ranging from 3.41 to 6.04 per 1-mg/dl increase in SU, all P < 10-3), which served as a positive control of our approach. Overall, our MR analysis had >99\% power to detect a causal effect of SU level on the risk of CKD of the same magnitude as the observed epidemiological association between SU and CKD. Limitations of this study include the lifelong effect of a genetic perturbation not being the same as an acute perturbation, the inability to study non-European populations, and some sample overlap between the datasets used in the study.

CONCLUSIONS: Evidence from our series of causal inference approaches using genetics does not support a causal effect of SU level on eGFR level or CKD risk. Reducing SU levels is unlikely to reduce the risk of CKD development.

}, keywords = {Adult, Age Factors, Female, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Male, Mendelian Randomization Analysis, Renal Insufficiency, Chronic, Sex Factors, Uric Acid, Young Adult}, issn = {1549-1676}, doi = {10.1371/journal.pmed.1002725}, author = {Jordan, Daniel M and Choi, Hyon K and Verbanck, Marie and Topless, Ruth and Won, Hong-Hee and Nadkarni, Girish and Merriman, Tony R and Do, Ron} } @article {9001, title = {Epigenetic Age and the Risk of Incident Atrial Fibrillation.}, journal = {Circulation}, volume = {144}, year = {2021}, month = {2021 12 14}, pages = {1899-1911}, abstract = {

BACKGROUND: The most prominent risk factor for atrial fibrillation (AF) is chronological age; however, underlying mechanisms are unexplained. Algorithms using epigenetic modifications to the human genome effectively predict chronological age. Chronological and epigenetic predicted ages may diverge in a phenomenon referred to as epigenetic age acceleration (EAA), which may reflect accelerated biological aging. We sought to evaluate for associations between epigenetic age measures and incident AF.

METHODS: Measures for 4 epigenetic clocks (Horvath, Hannum, DNA methylation [DNAm] PhenoAge, and DNAm GrimAge) and an epigenetic predictor of PAI-1 (plasminogen activator inhibitor-1) levels (ie, DNAm PAI-1) were determined for study participants from 3 population-based cohort studies. Cox models evaluated for associations with incident AF and results were combined via random-effects meta-analyses. Two-sample summary-level Mendelian randomization analyses evaluated for associations between genetic instruments of the EAA measures and AF.

RESULTS: Among 5600 participants (mean age, 65.5 years; female, 60.1\%; Black, 50.7\%), there were 905 incident AF cases during a mean follow-up of 12.9 years. Unadjusted analyses revealed all 4 epigenetic clocks and the DNAm PAI-1 predictor were associated with statistically significant higher hazards of incident AF, though the magnitudes of their point estimates were smaller relative to the associations observed for chronological age. The pooled EAA estimates for each epigenetic measure, with the exception of Horvath EAA, were associated with incident AF in models adjusted for chronological age, race, sex, and smoking variables. After multivariable adjustment for additional known AF risk factors that could also potentially function as mediators, pooled EAA measures for 2 clocks remained statistically significant. Five-year increases in EAA measures for DNAm GrimAge and DNAm PhenoAge were associated with 19\% (adjusted hazard ratio [HR], 1.19 [95\% CI, 1.09-1.31]; <0.01) and 15\% (adjusted HR, 1.15 [95\% CI, 1.05-1.25]; <0.01) higher hazards of incident AF, respectively. Mendelian randomization analyses for the 5 EAA measures did not reveal statistically significant associations with AF.

CONCLUSIONS: Our study identified adjusted associations between EAA measures and incident AF, suggesting that biological aging plays an important role independent of chronological age, though a potential underlying causal relationship remains unclear. These aging processes may be modifiable and not constrained by the immutable factor of time.

}, keywords = {Aged, Aging, Atrial Fibrillation, DNA Methylation, Epigenesis, Genetic, Epigenomics, Female, Follow-Up Studies, Humans, Incidence, Male, Mendelian Randomization Analysis, Middle Aged, Models, Cardiovascular, Models, Genetic}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.121.056456}, author = {Roberts, Jason D and Vittinghoff, Eric and Lu, Ake T and Alonso, Alvaro and Wang, Biqi and Sitlani, Colleen M and Mohammadi-Shemirani, Pedrum and Fornage, Myriam and Kornej, Jelena and Brody, Jennifer A and Arking, Dan E and Lin, Honghuang and Heckbert, Susan R and Prokic, Ivana and Ghanbari, Mohsen and Skanes, Allan C and Bartz, Traci M and Perez, Marco V and Taylor, Kent D and Lubitz, Steven A and Ellinor, Patrick T and Lunetta, Kathryn L and Pankow, James S and Par{\'e}, Guillaume and Sotoodehnia, Nona and Benjamin, Emelia J and Horvath, Steve and Marcus, Gregory M} } @article {9706, title = {Genetic Complexities of Cerebral Small Vessel Disease, Blood Pressure, and Dementia.}, journal = {JAMA Netw Open}, volume = {7}, year = {2024}, month = {2024 May 01}, pages = {e2412824}, abstract = {

IMPORTANCE: Vascular disease is a treatable contributor to dementia risk, but the role of specific markers remains unclear, making prevention strategies uncertain.

OBJECTIVE: To investigate the causal association between white matter hyperintensity (WMH) burden, clinical stroke, blood pressure (BP), and dementia risk, while accounting for potential epidemiologic biases.

DESIGN, SETTING, AND PARTICIPANTS: This study first examined the association of genetically determined WMH burden, stroke, and BP levels with Alzheimer disease (AD) in a 2-sample mendelian randomization (2SMR) framework. Second, using population-based studies (1979-2018) with prospective dementia surveillance, the genetic association of WMH, stroke, and BP with incident all-cause dementia was examined. Data analysis was performed from July 26, 2020, through July 24, 2022.

EXPOSURES: Genetically determined WMH burden and BP levels, as well as genetic liability to stroke derived from genome-wide association studies (GWASs) in European ancestry populations.

MAIN OUTCOMES AND MEASURES: The association of genetic instruments for WMH, stroke, and BP with dementia was studied using GWASs of AD (defined clinically and additionally meta-analyzed including both clinically diagnosed AD and AD defined based on parental history [AD-meta]) for 2SMR and incident all-cause dementia for longitudinal analyses.

RESULTS: In 2SMR (summary statistics-based) analyses using AD GWASs with up to 75 024 AD cases (mean [SD] age at AD onset, 75.5 [4.4] years; 56.9\% women), larger WMH burden showed evidence for a causal association with increased risk of AD (odds ratio [OR], 1.43; 95\% CI, 1.10-1.86; P = .007, per unit increase in WMH risk alleles) and AD-meta (OR, 1.19; 95\% CI, 1.06-1.34; P = .008), after accounting for pulse pressure for the former. Blood pressure traits showed evidence for a protective association with AD, with evidence for confounding by shared genetic instruments. In the longitudinal (individual-level data) analyses involving 10 699 incident all-cause dementia cases (mean [SD] age at dementia diagnosis, 74.4 [9.1] years; 55.4\% women), no significant association was observed between larger WMH burden and incident all-cause dementia (hazard ratio [HR], 1.02; 95\% CI, 1.00-1.04; P = .07). Although all exposures were associated with mortality, with the strongest association observed for systolic BP (HR, 1.04; 95\% CI, 1.03-1.06; P = 1.9 {\texttimes} 10-14), there was no evidence for selective survival bias during follow-up using illness-death models. In secondary analyses using polygenic scores, the association of genetic liability to stroke, but not genetically determined WMH, with dementia outcomes was attenuated after adjusting for interim stroke.

CONCLUSIONS: These findings suggest that WMH is a primary vascular factor associated with dementia risk, emphasizing its significance in preventive strategies for dementia. Future studies are warranted to examine whether this finding can be generalized to non-European populations.

}, keywords = {Aged, Aged, 80 and over, Alzheimer Disease, Blood Pressure, Cerebral Small Vessel Diseases, Dementia, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Mendelian Randomization Analysis, Prospective Studies, Risk Factors, Stroke}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2024.12824}, author = {Sargurupremraj, Muralidharan and Soumar{\'e}, A{\"\i}cha and Bis, Joshua C and Surakka, Ida and J{\"u}rgenson, Tuuli and Joly, Pierre and Knol, Maria J and Wang, Ruiqi and Yang, Qiong and Satizabal, Claudia L and Gudjonsson, Alexander and Mishra, Aniket and Bouteloup, Vincent and Phuah, Chia-Ling and van Duijn, Cornelia M and Cruchaga, Carlos and Dufouil, Carole and Chene, Genevi{\`e}ve and Lopez, Oscar L and Psaty, Bruce M and Tzourio, Christophe and Amouyel, Philippe and Adams, Hieab H and Jacqmin-Gadda, H{\'e}l{\`e}ne and Ikram, Mohammad Arfan and Gudnason, Vilmundur and Milani, Lili and Winsvold, Bendik S and Hveem, Kristian and Matthews, Paul M and Longstreth, W T and Seshadri, Sudha and Launer, Lenore J and Debette, Stephanie} } @article {9746, title = {Transcriptome-wide association study and Mendelian randomization in pancreatic cancer identifies susceptibility genes and causal relationships with type 2 diabetes and venous thromboembolism.}, journal = {EBioMedicine}, volume = {106}, year = {2024}, month = {2024 Aug}, pages = {105233}, abstract = {

BACKGROUND: Two important questions regarding the genetics of pancreatic adenocarcinoma (PDAC) are 1. Which germline genetic variants influence the incidence of this cancer; and 2. Whether PDAC causally predisposes to associated non-malignant phenotypes, such as type 2 diabetes (T2D) and venous thromboembolism (VTE).

METHODS: In this study of 8803 patients with PDAC and 67,523 controls, we first performed a large-scale transcriptome-wide association study to investigate the association between genetically determined gene expression in normal pancreas tissue and PDAC risk. Secondly, we used Mendelian Randomization (MR) to analyse the causal relationships among PDAC, T2D (74,124 cases and 824,006 controls) and VTE (30,234 cases and 172,122 controls).

FINDINGS: Sixteen genes showed an association with PDAC risk (FDR <0.10), including six genes not yet reported for PDAC risk (PPIP5K2, TFR2, HNF4G, LRRC10B, PRC1 and FBXL20) and ten previously reported genes (INHBA, SMC2, ABO, PDX1, MTMR6, ACOT2, PGAP3, STARD3, GSDMB, ADAM33). MR provided support for a causal effect of PDAC on T2D using genetic instruments in the HNF4G and PDX1 loci, and unidirectional causality of VTE on PDAC involving the ABO locus (OR 2.12, P~<~1e). No evidence of a causal effect of PDAC on VTE was found.

INTERPRETATION: These analyses identified candidate susceptibility genes and disease relationships for PDAC that warrant further investigation. HNF4G and PDX1 may induce PDAC-associated diabetes, whereas ABO may induce the causative effect of VTE on PDAC.

FUNDING: National Institutes of Health (USA).

}, keywords = {Diabetes Mellitus, Type 2, Female, Gene Expression Profiling, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Mendelian Randomization Analysis, Pancreatic Neoplasms, Polymorphism, Single Nucleotide, Transcriptome, Venous Thromboembolism}, issn = {2352-3964}, doi = {10.1016/j.ebiom.2024.105233}, author = {Tan, Marcus C B and Isom, Chelsea A and Liu, Yangzi and Tr{\'e}gou{\"e}t, David-Alexandre and Wu, Lang and Zhou, Dan and Gamazon, Eric R} } @article {9906, title = {Plasma Proteomic Assessment of Calcific Aortic Valve Disease in Older Adults.}, journal = {J Am Heart Assoc}, volume = {14}, year = {2025}, month = {2025 Mar 04}, pages = {e036336}, abstract = {

BACKGROUND: Calcific aortic valve disease (CAVD), and ensuing severe aortic stenosis (AS), is the foremost valvular disorder of aging, yet preventive therapies are lacking. A better understanding of the molecular underpinnings of aortic valve calcification (AVC) is necessary to develop pharmacologic interventions.

METHODS AND RESULTS: We undertook large-scale plasma proteomics in a cohort study of adults >=65 years old, the CHS (Cardiovascular Health Study), to identify individual proteins associated with echocardiographic AVC and incident moderate/severe AS. Proteomics measurements were performed with the aptamer-based SomaLogic platform of ~5000 proteins. Significant proteins were validated in a second cohort, the AGES-RS (Age, Gene/Environment Susceptibility-Reykjavik Study), which assessed AVC and AS by computed tomography. The potential causal associations of replicated proteins were tested in 2-sample Mendelian randomization using identified cis protein quantitative trait loci in consortia having computed tomography-quantified AVC or AS as outcomes. Six proteins showed Bonferroni-corrected significant relationships with AVC in CHS. Three of these, CXCL-12 (C-X-C chemokine ligand 12), KLKB1 (kallikrein), and leptin, replicated in AGES-RS, of which the former 2 are novel. Only 1 protein, CXCL6, which showed a near-significant association with AS in the replication cohort, was significantly (positively) associated with incident AS. Mendelian randomization analysis was conducted for KLKB1, CXCL12, and CXCL6, which supported a causal relationship for higher KLKB1 with lower AVC (beta=-0.25, =0.009).

CONCLUSIONS: This study of older adults newly identified and largely replicated associations of 3 circulating proteins with calcific aortic valve disease, of which the relationship of plasma KLKB1 may have a causal basis. Additional investigation is necessary to determine if KLKB1 could be harnessed for calcific aortic valve disease therapeutics.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Aortic Valve, Aortic Valve Stenosis, Biomarkers, Blood Proteins, Calcinosis, Chemokine CXCL12, Echocardiography, Female, Humans, Male, Mendelian Randomization Analysis, Proteomics, Severity of Illness Index}, issn = {2047-9980}, doi = {10.1161/JAHA.124.036336}, author = {Bortnick, Anna E and Austin, Thomas R and Hamerton, Emily and Gudmundsdottir, Valborg and Emilsson, Valur and Jennings, Lori L and Gudnason, Vilmundur and Owens, David S and Massera, Daniele and Dufresne, Line and Yang, Ta-Yu and Engert, James C and Thanassoulis, George and Tracy, Russell P and Gerszten, Robert E and Psaty, Bruce M and Kizer, Jorge R} }