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2. Association of common genetic variants with brain microbleeds

Author

Knol, M.J., Lu, D.W., Traylor, M., Adams, H.H.H., Romero, J.R.J., Smith, A.V., Fornage, M., Hofer, E., Liu, J.F., Hostettler, I.C., Luciano, M., Trompet, S., Giese, A.K., Hilal, S., Akker, E.B. van den, Vojinovic, D., Li, S., Sigurdsson, S., Lee, S.J. van der, Jack, C.R., Wilson, D., Yilmaz, P., Satizabal, C.L., Liewald, D.C.M., Grond, J. van der, Chen, C., Saba, Y., Lugt, A. van der, Bastin, M.E., Windham, B.G., Cheng, C.Y., Pirpamer, L., Kantarci, K., Himali, J.J., Yang, Q., Morris, Z., Beiser, A.S., Tozer, D.J., Vernooij, M.W., Amin, N., Beekman, M., Koh, J.Y., Stott, D.J., Houlden, H., Schmidt, R., Gottesman, R.F., MacKinnon, A.D., DeCarli, C., Gudnason, V., Deary, I.J., Duijn, C.M. van, Slagboom, P.E., Wong, T.Y., Rost, N.S., Jukema, J.W., Mosley, T.H., Werring, D.J., Schmidt, H., Wardlaw, J.M., Ikram, M.A., Seshadri, S., Launer, L.J., Markus, H.S., Neurology, Amsterdam Neuroscience - Neurodegeneration, Epidemiology, Neurosciences, Clinical Genetics, and Radiology & Nuclear Medicine

Subjects
0301 basic medicine, medicine.medical_specialty, education.field_of_study, business.industry, Population, Genome-wide association study, Single-nucleotide polymorphism, Odds ratio, Gastroenterology, Hyperintensity, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Internal medicine, Genetic predisposition, medicine, Neurology (clinical), Allele, business, education, 030217 neurology & neurosurgery, Genetic association
Abstract

ObjectiveTo identify common genetic variants associated with the presence of brain microbleeds (BMBs).MethodsWe performed genome-wide association studies in 11 population-based cohort studies and 3 case–control or case-only stroke cohorts. Genotypes were imputed to the Haplotype Reference Consortium or 1000 Genomes reference panel. BMBs were rated on susceptibility-weighted or T2*-weighted gradient echo MRI sequences, and further classified as lobar or mixed (including strictly deep and infratentorial, possibly with lobar BMB). In a subset, we assessed the effects of APOE ε2 and ε4 alleles on BMB counts. We also related previously identified cerebral small vessel disease variants to BMBs.ResultsBMBs were detected in 3,556 of the 25,862 participants, of which 2,179 were strictly lobar and 1,293 mixed. One locus in the APOE region reached genome-wide significance for its association with BMB (lead single nucleotide polymorphism rs769449; odds ratio [OR]any BMB [95% confidence interval (CI)] 1.33 [1.21–1.45]; p = 2.5 × 10−10). APOE ε4 alleles were associated with strictly lobar (OR [95% CI] 1.34 [1.19–1.50]; p = 1.0 × 10−6) but not with mixed BMB counts (OR [95% CI] 1.04 [0.86–1.25]; p = 0.68). APOE ε2 alleles did not show associations with BMB counts. Variants previously related to deep intracerebral hemorrhage and lacunar stroke, and a risk score of cerebral white matter hyperintensity variants, were associated with BMB.ConclusionsGenetic variants in the APOE region are associated with the presence of BMB, most likely due to the APOE ε4 allele count related to a higher number of strictly lobar BMBs. Genetic predisposition to small vessel disease confers risk of BMB, indicating genetic overlap with other cerebral small vessel disease markers.

Published
2020

4. Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function (vol 9, 2098, 2018)

Author

Davies, G., Lam, M., Harris, S.E., Trampush, J.W., Luciano, M., Hill, W.D., Hagenaars, S.P., Ritchie, S.J., Marioni, R.E., Fawns-Ritchie, C., Liewald, D.C.M., Okely, J.A., Ahola-Olli, A.V., Barnes, C.L.K., Bertram, L., Bis, J.C., Burdick, K.E., Christoforou, A., DeRosse, P., Djurovic, S., Espeseth, T., Giakoumaki, S., Giddaluru, S., Gustavson, D.E., Hayward, C., Hofer, E., Ikram, M.A., Karlsson, R., Knowles, E., Lahti, J., Leber, M., Li, S., Mather, K.A., Melle, I., Morris, D., Oldmeadow, C., Palviainen, T., Payton, A., Pazoki, R., Petrovic, K., Reynolds, C.A., Sargurupremraj, M., Scholz, M., Smith, J.A., Smith, A.V., Terzikhan, N., Thalamuthu, A., Trompet, S., Lee, S.J. van der, Ware, E.B., Windham, B.G., Wright, M.J., Yang, J.Y., Yu, J., Ames, D., Amin, N., Amouyel, P., Andreassen, O.A., Armstrong, N.J., Assareh, A.A., Attia, J.R., Attix, D., Avramopoulos, D., Bennett, D.A., Bohmer, A.C., Boyle, P.A., Brodaty, H., Campbell, H., Cannon, T.D., Cirulli, E.T., Congdon, E., Conley, E.D., Corley, J., Cox, S.R., Dale, A.M., Dehghan, A., Dick, D., Dickinson, D., Eriksson, J.G., Evangelou, E., Faul, J.D., Ford, I., Freimer, N.A., Gao, H., Giegling, I., Gillespie, N.A., Gordon, S.D., Gottesman, R.F., Griswold, M.E., Gudnason, V., Harris, T.B., Hartmann, A.M., Hatzimanolis, A., Heiss, G., Holliday, E.G., Joshi, P.K., Kahonen, M., Kardia, S.L.R., Karlsson, I., Kleineidam, L., Knopman, D.S., Kochan, N.A., Konte, B., Kwok, J.B., Hellard, S. le, Lee, T., Lehtimaki, T., Li, S.C., Lill, C.M., Liu, T., Koini, M., London, E., Longstreth, W.T., Lopez, O.L., Loukola, A., Luck, T., Lundervold, A.J., Lundquist, A., Lyytikainen, L.P., Martin, N.G., Montgomery, G.W., Murray, A.D., Need, A.C., Noordam, R., Nyberg, L., Ollier, W., Papenberg, G., Pattie, A., Polasek, O., Poldrack, R.A., Psaty, B.M., Reppermund, S., Riedel-Heller, S.G., Rose, R.J., Rotter, J.I., Roussos, P., Rovio, S.P., Saba, Y., Sabb, F.W., Sachdev, P.S., Satizabal, C.L., Schmid, M., Scott, R.J., Scult, M.A., Simino, J., Slagboom, P.E., Smyrnis, N., Soumare, A., Stefanis, N.C., Stott, D.J., Straub, R.E., Sundet, K., Taylor, A.M., Taylor, K.D., Tzoulaki, I., Tzourio, C., Uitterlinden, A., Vitart, V., Voineskos, A.N., Kaprio, J., Wagner, M., Wagner, H., Weinhold, L., Wen, K.H., Widen, E., Yang, Q., Zhao, W., Adams, H.H.H., Arking, D.E., Bilder, R.M., Bitsios, P., Boerwinkle, E., Chiba-Falek, O., Corvin, A., Jager, P.L. de, Debette, S., Donohoe, G., Elliott, P., Fitzpatrick, A.L., Gill, M., Glahn, D.C., Hagg, S., Hansell, N.K., Hariri, A.R., Ikram, M.K., Jukema, J.W., Vuoksimaa, E., Keller, M.C., Kremen, W.S., Launer, L., Lindenberger, U., Palotie, A., Pedersen, N.L., Pendleton, N., Porteous, D.J., Raikkonen, K., Raitakari, O.T., Ramirez, A., Reinvang, I., Rudan, I., Rujescu, D., Schmidt, R., Schmidt, H., Schofield, P.W., Schofield, P.R., Starr, J.M., Steen, V.M., Trollor, J.N., Turner, S.T., Duijn, C.M. van, Villringer, A., Weinberger, D.R., Weir, D.R., Wilson, J.F., Malhotra, A., McIntosh, A.M., Gale, C.R., Seshadri, S., Mosley, T.H., Bressler, J., Lencz, T., and Deary, I.J.

Published
2019

5. Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting

Author

Chauhan, G., Adams, H.H.H., Satizabal, C.L., Bis, J.C., Teumer, A., Sargurupremraj, M., Hofer, E., Trompet, S., Hilal, S., Smith, A.V., Jian, X.Q., Malik, R., Traylor, M., Pulit, S.L., Amouyel, P., Mazoyer, B., Zhu, Y.C., Kaffashian, S., Schilling, S., Beecham, G.W., Montine, T.J., Schellenberg, G.D., Kjartansson, O., Gudnason, V., Knopman, D.S., Griswold, M.E., Windham, B.G., Gottesman, R.F., Mosley, T.H., Schmidt, R., Saba, Y., Schmidt, H., Takeuchi, F., Yamaguchi, S., Nabika, T., Kato, N., Rajan, K.B., Aggarwal, N.T., Jager, P.L. de, Evans, D.A., Psaty, B.M., Rotter, J.I., Rice, K., Lopez, O.L., Liao, J.M., Chen, C., Cheng, C.Y., Wong, T.Y., Ikram, M.K., Lee, S.J. van der, Amin, N., Chouraki, V., DeStefano, A.L., Aparicio, H.J., Romero, J.R., Maillard, P., DeCarli, C., Wardlaw, J.M., Hernandez, M.D.V., Luciano, M., Liewald, D., Deary, I.J., Starr, J.M., Bastin, M.E., Maniega, S.M., Slagboom, P.E., Beekman, M., Deelen, J., Uh, H.W., Lemmens, R., Brodaty, H., Wright, M.J., Ames, D., Boncoraglio, G.B., Hopewell, J.C., Beecham, A.H., Blanton, S.H., Wright, C.B., Sacco, R.L., Wen, W., Thalamuthu, A., Armstrong, N.J., Chong, E., Schofield, P.R., Kwok, J.B., Grond, J. van der, Stott, D.J., Ford, I., Jukema, J.W., Vernooij, M.W., Hofman, A., Uitterlinden, A.G., Lugt, A. van der, Wittfeld, K., Grabe, H.J., Hosten, N., Sarnowski, B. von, Volker, U., Levi, C., Jimenez-Conde, J., Sharma, P., Sudlow, C.L.M., Rosand, J., Woo, D., Cole, J.W., Meschia, J.F., Slowik, A., Thijs, V., Lindgren, A., Melander, O., Grewal, R.P., Rundek, T., Rexrode, K., Rothwell, P.M., Arnett, D.K., Jern, C., Johnson, J.A., Benavente, O.R., Wasssertheil-Smoller, S., Lee, J.M., Wong, Q., Mitchell, B.D., Rich, S.S., McArdle, P.F., Geerlings, M.I., Graaf, Y. van der, Bakker, P.I.W. de, Asselbergs, F.W., Srikanth, V., Thomson, R., McWhirter, R., Moran, C., Callisaya, M., Phan, T., Rutten-Jacobs, L.C.A., Bevan, S., Tzourio, C., Mather, K.A., Sachdev, P.S., Duijn, C.M. van, Worrall, B.B., Dichgans, M., Kittner, S.J., Markus, H.S., Ikram, M.A., Fornage, M., Launer, L.J., Seshadri, S., Longstreth, W.T., Debette, S., Stroke Genetics Network SiGN, ISGC, METASTROKE, ADGC, and CHARGE Consortium

Subjects
Meta-analysis, Mendelian Randomization, Blood Pressure, Polymorphisms, Genome-wide Association, Silent, Insights, Small Vessel Disease, Matter Hyperintensity Volume, Ischemic Stroke, Doenças Cardio e Cérebro-vasculares
Abstract

Collaborators (845): Astrid M. Vicente Free PMC article:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369905/ Objective: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. Methods: We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. Results: The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10-8; and LINC00539/ZDHHC20, p = 5.82 × 10-9. Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p [BI] = 9.38 × 10-25; p [SSBI] = 5.23 × 10-14 for hypertension), smoking (p [BI] = 4.4 × 10-10; p [SSBI] = 1.2 × 10-4), diabetes (p [BI] = 1.7 × 10-8; p [SSBI] = 2.8 × 10-3), previous cardiovascular disease (p [BI] = 1.0 × 10-18; p [SSBI] = 2.3 × 10-7), stroke (p [BI] = 3.9 × 10-69; p [SSBI] = 3.2 × 10-24), and MRI-defined white matter hyperintensity burden (p [BI] = 1.43 × 10-157; p [SSBI] = 3.16 × 10-106), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p ≤ 0.0022), without indication of directional pleiotropy. Conclusion: In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI. info:eu-repo/semantics/publishedVersion

Published
2019

6. Author Correction: Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function (Nature Communications, (2018), 9, 1, (2098), 10.1038/s41467-018-04362-x)

Author

Davies, G. Lam, M. Harris, S.E. Trampush, J.W. Luciano, M. Hill, W.D. Hagenaars, S.P. Ritchie, S.J. Marioni, R.E. Fawns-Ritchie, C. Liewald, D.C.M. Okely, J.A. Ahola-Olli, A.V. Barnes, C.L.K. Bertram, L. Bis, J.C. Burdick, K.E. Christoforou, A. DeRosse, P. Djurovic, S. Espeseth, T. Giakoumaki, S. Giddaluru, S. Gustavson, D.E. Hayward, C. Hofer, E. Ikram, M.A. Karlsson, R. Knowles, E. Lahti, J. Leber, M. Li, S. Mather, K.A. Melle, I. Morris, D. Oldmeadow, C. Palviainen, T. Payton, A. Pazoki, R. Petrovic, K. Reynolds, C.A. Sargurupremraj, M. Scholz, M. Smith, J.A. Smith, A.V. Terzikhan, N. Thalamuthu, A. Trompet, S. van der Lee, S.J. Ware, E.B. Windham, B.G. Wright, M.J. Yang, J. Yu, J. Ames, D. Amin, N. Amouyel, P. Andreassen, O.A. Armstrong, N.J. Assareh, A.A. Attia, J.R. Attix, D. Avramopoulos, D. Bennett, D.A. Böhmer, A.C. Boyle, P.A. Brodaty, H. Campbell, H. Cannon, T.D. Cirulli, E.T. Congdon, E. Conley, E.D. Corley, J. Cox, S.R. Dale, A.M. Dehghan, A. Dick, D. Dickinson, D. Eriksson, J.G. Evangelou, E. Faul, J.D. Ford, I. Freimer, N.A. Gao, H. Giegling, I. Gillespie, N.A. Gordon, S.D. Gottesman, R.F. Griswold, M.E. Gudnason, V. Harris, T.B. Hartmann, A.M. Hatzimanolis, A. Heiss, G. Holliday, E.G. Joshi, P.K. Kähönen, M. Kardia, S.L.R. Karlsson, I. Kleineidam, L. Knopman, D.S. Kochan, N.A. Konte, B. Kwok, J.B. Le Hellard, S. Lee, T. Lehtimäki, T. Li, S.-C. Lill, C.M. Liu, T. Koini, M. London, E. Longstreth, W.T., Jr. Lopez, O.L. Loukola, A. Luck, T. Lundervold, A.J. Lundquist, A. Lyytikäinen, L.-P. Martin, N.G. Montgomery, G.W. Murray, A.D. Need, A.C. Noordam, R. Nyberg, L. Ollier, W. Papenberg, G. Pattie, A. Polasek, O. Poldrack, R.A. Psaty, B.M. Reppermund, S. Riedel-Heller, S.G. Rose, R.J. Rotter, J.I. Roussos, P. Rovio, S.P. Saba, Y. Sabb, F.W. Sachdev, P.S. Satizabal, C.L. Schmid, M. Scott, R.J. Scult, M.A. Simino, J. Slagboom, P.E. Smyrnis, N. Soumaré, A. Stefanis, N.C. Stott, D.J. Straub, R.E. Sundet, K. Taylor, A.M. Taylor, K.D. Tzoulaki, I. Tzourio, C. Uitterlinden, A. Vitart, V. Voineskos, A.N. Kaprio, J. Wagner, M. Wagner, H. Weinhold, L. Wen, K.H. Widen, E. Yang, Q. Zhao, W. Adams, H.H.H. Arking, D.E. Bilder, R.M. Bitsios, P. Boerwinkle, E. Chiba-Falek, O. Corvin, A. De Jager, P.L. Debette, S. Donohoe, G. Elliott, P. Fitzpatrick, A.L. Gill, M. Glahn, D.C. Hägg, S. Hansell, N.K. Hariri, A.R. Ikram, M.K. Jukema, J.W. Vuoksimaa, E. Keller, M.C. Kremen, W.S. Launer, L. Lindenberger, U. Palotie, A. Pedersen, N.L. Pendleton, N. Porteous, D.J. Räikkönen, K. Raitakari, O.T. Ramirez, A. Reinvang, I. Rudan, I. Dan Rujescu Schmidt, R. Schmidt, H. Schofield, P.W. Schofield, P.R. Starr, J.M. Steen, V.M. Trollor, J.N. Turner, S.T. Van Duijn, C.M. Villringer, A. Weinberger, D.R. Weir, D.R. Wilson, J.F. Malhotra, A. McIntosh, A.M. Gale, C.R. Seshadri, S. Mosley, T.H., Jr. Bressler, J. Lencz, T. Deary, I.J.

Subjects
ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries)
Abstract

Christina M. Lill, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this article. This has now been corrected in both the PDF and HTML versions of the article. © 2019, The Author(s).

Published
2019

7. Leisure-time physical activity sustained since midlife and preservation of cognitive function: The Atherosclerosis Risk in Communities Study

Author

Heiss, G., Mosley, T.H., Gabriel, K.P., Knopman, D., Evenson, K.R., Gross, A.L., Folsom, A.R., Palta, P., Deal, J.A., Sharrett, A.R., and Windham, B.G.

Subjects
human activities
Abstract

Introduction: We tested the hypotheses that higher levels of and persistence of midlife leisure-time physical activity (LTPA) are associated long-term with lower cognitive decline and less incident dementia. Methods: A total of 10,705 participants (mean age: 60 years) had LTPA (no, low, middle, or high) measured in 1987-1989 and 1993-1995. LTPA was assessed in relation to incident dementia and 14-year change in general cognitive performance. Results: Over a median follow-up of 17.4 years, 1063 dementia cases were observed. Compared with no LTPA, high LTPA in midlife was associated with lower incidence of dementia (hazard ratio [95% confidence interval], 0.71 [0.61, 0.86]) and lower declines in general cognitive performance (���0.07 standard deviation difference [���0.12 to ���0.04]). These associations were stronger when measured against persistence of midlife LTPA over 6 years. Discussion: LTPA is a readily modifiable factor associated inversely with long-term dementia incidence and cognitive decline.

Published
2019
Full Text
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8. The complex genetics of gait speed: genome-wide meta-analysis approach (vol 9, pg 209, 2017)

Author

Ben-Avraham, D., Karasik, D., Verghese, J., Lunetta, K.L., Smith, J.A., Eicher, J.D., Vered, R., Deelen, J., Arnold, A.M., Buchman, A.S., Tanaka, T., Faul, J.D., Nethander, M., Fornage, M., Adams, H.H., Matteini, A.M., Callisaya, M.L., Smith, A.V., Yu, L., Jager, P.L. de, Evans, D.A., Gudnason, V., Hofman, A., Pattie, A., Corley, J., Launer, L.J., Knopman, D.S., Parimi, N., Turner, S.T., Bandinelli, S., Beekman, M., Gutman, D., Sharvit, L., Mooijaart, S.P., Liewald, D.C., Houwing-Duistermaat, J.J., Ohlsson, C., Moed, M., Verlinden, V.J., Mellstrom, D., Geest, J.N. van der, Karlsson, M., Hernandez, D., McWhirter, R., Liu, Y.M., Thomson, R., Tranah, G.J., Uitterlinden, A.G., Weir, D.R., Zhao, W., Starr, J.M., Johnson, A.D., Ikram, M.A., Bennett, D.A., Cummings, S.R., Deary, I.J., Harris, T.B., Kardia, S.L.R., Mosley, T.H., Srikanth, V.K., Windham, B.G., Newman, A.B., Walston, J.D., Davies, G., Evans, D.S., Slagboom, E.P., Ferrucci, L., Kiel, D.P., Murabito, J.M., and Atzmon, G.

Published
2017

9. White Matter Lesion Progression Genome-Wide Search for Genetic Influences

Author

Hofer, E., Cavalieri, M., Bis, J.C., DeCarli, C., Fornage, M., Sigurdsson, S., Srikanth, V., Trompet, S., Verhaaren, B.F.J., Wolf, C., Yang, Q., Adams, H.H.H., Amouyel, P., Beiser, A., Buckley, B.M., Callisaya, M., Chauhan, G., Craen, A.J.M. de, Dufouil, C., Duijn, C.M. van, Ford, I., Freudenberger, P., Gottesman, R.F., Gudnason, V., Heiss, G., Hofman, A., Lumley, T., Martinez, O., Mazoyer, B., Moran, C., Niessen, W.J., Phan, T., Psaty, B.M., Satizabal, C.L., Sattar, N., Schilling, S., Shibata, D.K., Slagboom, P.E., Smith, A., Stott, D.J., Taylor, K.D., Thomson, R., Toglhofer, A.M., Tzourio, C., Buchem, M. van, Wang, J., Westendorp, R.G.J., Windham, B.G., Vernooij, M.W., Zijdenbos, A., Beare, R., Debette, S., Ikram, M.A., Jukema, J.W., Launer, L.J., Longstreth, W.T., Mosley, T.H., Seshadri, S., Schmidt, H., Schmidt, R., and Cohorts Heart Aging Res Genomic Ep

Subjects
Adult, Male, Aging, Clinical Sciences, Cardiorespiratory Medicine and Haematology, Cardiovascular, Cohort Studies, Leukoencephalopathies, Clinical Research, Genetics, Humans, magnetic resonance imaging, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Prospective Studies, Aetiology, Aged, Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium, Neurology & Neurosurgery, white matter lesions, Prevention, Human Genome, Neurosciences, Middle Aged, biological factors, White Matter, Disease Progression, Female, cerebral small vessel diseases, Genome-Wide Association Study
Abstract

Background and purposeWhite matter lesion (WML) progression on magnetic resonance imaging is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.MethodsHeritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from 10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in 7 cohorts risk models including demographics, vascular risk factors plus single-nucleotide polymorphisms that have been shown to be associated cross-sectionally with WML in the current and previous association studies.ResultsA total of 1085 subjects showed WML progression. The heritability estimate for WML progression was low at 6.5%, and no single-nucleotide polymorphisms achieved genome-wide significance (P

Published
2015

10. Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949)

Author

Davies, G., Armstrong, N., Bis, J.C., Bressler, J., Chouraki, V., Giddaluru, S., Hofer, E., Ibrahim-Verbaas, C.A., Kirin, M., Lahti, J., Lee, S.J. van der, Hellard, S. le, Liu, T., Marioni, R.E., Oldmeadow, C., Postmus, I., Smith, A.V., Smith, J.A., Thalamuthu, A., Thomson, R., Vitart, V., Wang, J., Yu, L., Zgaga, L., Zhao, W., Boxall, R., Harris, S.E., Hill, W.D., Liewald, D.C., Luciano, M., Adams, H., Ames, D., Amin, N., Amouyel, P., Assareh, A.A., Au, R., Becker, J.T., Beiser, A., Berr, C., Bertram, L., Boerwinkle, E., Buckley, B.M., Campbell, H., Corley, J., Jager, P.L. de, Dufouil, C., Eriksson, J.G., Espeseth, T., Faul, J.D., Ford, I., Gottesman, R.F., Griswold, M.E., Gudnason, V., Harris, T.B., Heiss, G., Hofman, A., Holliday, E.G., Huffman, J., Kardia, S.L.R., Kochan, N., Knopman, D.S., Kwok, J.B., Lambert, J.C., Lee, T., Li, G., Li, S.C., Loitfelder, M., Lopez, O.L., Lundervold, A.J., Lundqvist, A., Mather, K.A., Mirza, S.S., Nyberg, L., Oostra, B.A., Palotie, A., Papenberg, G., Pattie, A., Petrovic, K., Polasek, O., Psaty, B.M., Redmond, P., Reppermund, S., Rotter, J.I., Schmidt, H., Schuur, M., Schofield, P.W., Scott, R.J., Steen, V.M., Stott, D.J., Swieten, J.C. van, Taylor, K.D., Trollor, J., Trompet, S., Uitterlinden, A.G., Weinstein, G., Widen, E., Windham, B.G., Jukema, J.W., Wright, A.F., Wright, M.J., Yang, Q., Amieva, H., Attia, J.R., Bennett, D.A., Brodaty, H., Craen, A.J.M. de, Hayward, C., Ikram, M.A., Lindenberger, U., Nilsson, L.G., Porteous, D.J., Raikkonen, K., Reinvang, I., Rudan, I., Sachdev, P.S., Schmidt, R., Schofield, P.R., Srikanth, V., Starr, J.M., Turner, S.T., Weir, D.R., Wilson, J.F., Duijn, C. van, Launer, L., Fitzpatrick, A.L., Seshadri, S., Jr, T.H.M., Deary, I.J., and Generation Scotland

Subjects
Medisinske fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk genetikk: 714 [VDP], Social sciences: 200::Psychology: 260::Cognitive psychology: 267 [VDP], Midical sciences: 700::Basic medical, dental and veterinary sciences: 710::Medical genetics: 714 [VDP], Samfunnsvitenskap: 200::Psykologi: 260::Kognitiv psykologi: 267 [VDP]
Abstract

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53 949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10−9, MIR2113; rs17522122, P=2.55 × 10−8, AKAP6; rs10119, P=5.67 × 10−9, APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10−6). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10−17). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer’s disease: TOMM40, APOE, ABCG1 and MEF2C. publishedVersion

Published
2015

11. Device-guided slow-breathing effects on end-tidal CO2 and heart-rate variability.

Author

Anderson, D.E., McNeely, J.D., and Windham, B.G.

Subjects
RESPIRATION, BREATHING apparatus, BLOOD pressure, SYMPATHETIC nervous system, HYPOTHESIS, LABORATORY animals
Abstract

Previous studies have reported that regular practice of a device-guided slow-breathing (DGB) exercise decreases resting blood pressure (BP) in hypertensive patients. The performance of DGB is associated with acute decreases in sympathetic vascular tone, and it has been suggested that the decreases in resting BP produced by regular practice of DGB over periods of weeks are due to chronic decreases in sympathetic nervous system activity. However, the kidneys respond to sympathetically mediated changes in BP by readjusting blood volume levels within a few days. Thus, the mechanism by which DGB could produce long-term BP changes remains to be clarified. Previous research with laboratory animals and human subjects has shown that slow, shallow breathing that increases pCO2 potentiates BP sensitivity to high sodium intake. These findings raise the possibility that deeper breathing during DGB that decreases BP might involve opposite changes in pCO2. The present study tested the hypothesis that performance of DGB acutely decreases a marker of pCO2, end-tidal CO2 (PetCO2). Breathing rate, tidal volume, and PetCO2 were monitored before, during, and after a 15-min session of DGB by patients with elevated BP. BP, heart rate, and heart-rate variability (HRV) were also measured under these conditions. A control group was also studied before, during, and after a 15-min session of spontaneous breathing (SB). The DGB group, but not the SB group, showed progressive and substantial increases in tidal volume and low-frequency HRV and decreases in PetCO2 and systolic BP. The PetCO2 effects persisted into the posttask, rest period. The findings are consistent with the hypothesis that habitual changes in breathing patterns of the kind observed during DGB could potentiate an antihypertensive adaptation via effects on pCO2 and its role in cardiovascular homeostasis. [ABSTRACT FROM AUTHOR]

Published
2009
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12. Reducing the Population Burden of Coronary Heart Disease by Modifying Adiposity: Estimates From the ARIC Study

Author

Gellert, K.S., Keil, A.P., Siega-Riz, A.M., Aubert, R.E., Windham, B.G., Heiss, G., Avery, C.L., Lutsey, P.L., Lesko, C.R., and Zeng, D.

Subjects
2. Zero hunger
Abstract

Background: Excess adiposity, which affects 69% of US adults, increases coronary heart disease (CHD) risk in an association that manifests below conventional obesity cut points. The population-level impact on CHD risk that is attainable through modest adiposity reductions in populations is not well characterized. We estimated the effect of hypothetical reductions in both body mass index (BMI) and waist circumference (WC) on CHD incidence. Methods and Results: The study population included 13 610 ARIC (Atherosclerosis Risk in Communities) participants. Our hypothetical reduction in BMI or WC was applied relative to the temporal trend, with no hypothetical reduction among those with BMI >24 or WC >88 cm, respectively. This threshold for hypothetical reduction is near the clinical guidelines for excess adiposity. CHD risk differences compared the hypothetical reduction with no reduction. Sensitivity analysis was conducted to estimate the effect of applying the hypothetical BMI reduction at the established overweight cut point of 25. Cumulative 12-year CHD incidence with no intervention was 6.3% (95% CI, 5.9–6.8%). Risk differences following the hypothetical BMI and WC reductions were −0.6% (95% CI, −1.0% to −0.1%) and −1.0% (95% CI, −1.4% to −0.5%), respectively. These results were robust for the sensitivity analyses. Consequently, we estimated that this hypothetical reduction of 5% in BMI and WC, respectively, could have prevented 9% and 16%, respectively, of the CHD events occurring in this study population over 12 years, after adjustment for established CHD risk factors. Conclusions: Meaningful CHD risk reductions could derive from modest reductions in adiposity attainable through lifestyle modification.

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