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1. Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders

Author

UMC Utrecht, Neurogenetica, Neurologen, Brain, Projectafdeling ALS, Regenerative Medicine and Stem Cells, Nabais, Marta F., Laws, Simon M., Lin, Tian, Vallerga, Costanza L., Armstrong, Nicola J., Blair, Ian P., Kwok, John B., Mather, Karen A., Mellick, George D., Sachdev, Perminder S., Wallace, Leanne, Henders, Anjali K., Zwamborn, Ramona A.J., Hop, Paul J., Lunnon, Katie, Pishva, Ehsan, Roubroeks, Janou A.Y., Soininen, Hilkka, Tsolaki, Magda, Mecocci, Patrizia, Lovestone, Simon, Kłoszewska, Iwona, Vellas, Bruno, Furlong, Sarah, Garton, Fleur C., Henderson, Robert D., Mathers, Susan, McCombe, Pamela A., Needham, Merrilee, Ngo, Shyuan T., Nicholson, Garth, Pamphlett, Roger, Rowe, Dominic B., Steyn, Frederik J., Williams, Kelly L., Anderson, Tim J., Bentley, Steven R., Dalrymple-Alford, John, Fowder, Javed, Gratten, Jacob, Halliday, Glenda, Hickie, Ian B., Kennedy, Martin, Lewis, Simon J.G., Montgomery, Grant W., Pearson, John, Pitcher, Toni L., van Rheenen, Wouter, van den Berg, Leonard H., Veldink, Jan H., the Australian Imaging Biomarkers and Lifestyle study, the Alzheimer’s Disease Neuroimaging Initiative, UMC Utrecht, Neurogenetica, Neurologen, Brain, Projectafdeling ALS, Regenerative Medicine and Stem Cells, Nabais, Marta F., Laws, Simon M., Lin, Tian, Vallerga, Costanza L., Armstrong, Nicola J., Blair, Ian P., Kwok, John B., Mather, Karen A., Mellick, George D., Sachdev, Perminder S., Wallace, Leanne, Henders, Anjali K., Zwamborn, Ramona A.J., Hop, Paul J., Lunnon, Katie, Pishva, Ehsan, Roubroeks, Janou A.Y., Soininen, Hilkka, Tsolaki, Magda, Mecocci, Patrizia, Lovestone, Simon, Kłoszewska, Iwona, Vellas, Bruno, Furlong, Sarah, Garton, Fleur C., Henderson, Robert D., Mathers, Susan, McCombe, Pamela A., Needham, Merrilee, Ngo, Shyuan T., Nicholson, Garth, Pamphlett, Roger, Rowe, Dominic B., Steyn, Frederik J., Williams, Kelly L., Anderson, Tim J., Bentley, Steven R., Dalrymple-Alford, John, Fowder, Javed, Gratten, Jacob, Halliday, Glenda, Hickie, Ian B., Kennedy, Martin, Lewis, Simon J.G., Montgomery, Grant W., Pearson, John, Pitcher, Toni L., van Rheenen, Wouter, van den Berg, Leonard H., Veldink, Jan H., the Australian Imaging Biomarkers and Lifestyle study, and the Alzheimer’s Disease Neuroimaging Initiative

Published
2021

2. Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders

Author

Nabais, Marta F., Laws, Simon M., Lin, Tian, Vallerga, Costanza L., Armstrong, Nicola J., Blair, Ian P., Kwok, John B., Mather, Karen A., Mellick, George D., Sachdev, Perminder S., Wallace, Leanne, Henders, Anjali K., Zwamborn, Ramona A. J., Hop, Paul J., Lunnon, Katie, Pishva, Ehsan, Roubroeks, Janou A. Y., Soininen, Hilkka, Tsolaki, Magda, Mecocci, Patrizia, Lovestone, Simon, Kłoszewska, Iwona, Vellas, Bruno, Furlong, Sarah, Garton, Fleur C., Henderson, Robert D., Mathers, Susan, McCombe, Pamela A., Needham, Merrilee, Ngo, Shyuan T., Nicholson, Garth, Pamphlett, Roger, Rowe, Dominic B., Steyn, Frederik J., Williams, Kelly L., Anderson, Tim J., Bentley, Steven R., Dalrymple-Alford, John, Fowder, Javed, Gratten, Jacob, Halliday, Glenda, Hickie, Ian B., Kennedy, Martin, Lewis, Simon J. G., Montgomery, Grant W., Pearson, John, Pitcher, Toni L., Silburn, Peter, Zhang, Futao, Visscher, Peter M., Yang, Jian, Stevenson, Anna J., Hillary, Robert F., Marioni, Riccardo E., Harris, Sarah E., Deary, Ian J., Jones, Ashley R., Shatunov, Aleksey, Iacoangeli, Alfredo, van Rheenen, Wouter, van den Berg, Leonard H., Shaw, Pamela J., Shaw, Cristopher E., Morrison, Karen E., Al-Chalabi, Ammar, Veldink, Jan H., Hannon, Eilis, Mill, Jonathan, Wray, Naomi R., McRae, Allan F., the Alzheimer's Disease Neuroimaging Initiative, the Australian Imaging Biomarkers and Lifestyle study, Nabais, Marta F., Laws, Simon M., Lin, Tian, Vallerga, Costanza L., Armstrong, Nicola J., Blair, Ian P., Kwok, John B., Mather, Karen A., Mellick, George D., Sachdev, Perminder S., Wallace, Leanne, Henders, Anjali K., Zwamborn, Ramona A. J., Hop, Paul J., Lunnon, Katie, Pishva, Ehsan, Roubroeks, Janou A. Y., Soininen, Hilkka, Tsolaki, Magda, Mecocci, Patrizia, Lovestone, Simon, Kłoszewska, Iwona, Vellas, Bruno, Furlong, Sarah, Garton, Fleur C., Henderson, Robert D., Mathers, Susan, McCombe, Pamela A., Needham, Merrilee, Ngo, Shyuan T., Nicholson, Garth, Pamphlett, Roger, Rowe, Dominic B., Steyn, Frederik J., Williams, Kelly L., Anderson, Tim J., Bentley, Steven R., Dalrymple-Alford, John, Fowder, Javed, Gratten, Jacob, Halliday, Glenda, Hickie, Ian B., Kennedy, Martin, Lewis, Simon J. G., Montgomery, Grant W., Pearson, John, Pitcher, Toni L., Silburn, Peter, Zhang, Futao, Visscher, Peter M., Yang, Jian, Stevenson, Anna J., Hillary, Robert F., Marioni, Riccardo E., Harris, Sarah E., Deary, Ian J., Jones, Ashley R., Shatunov, Aleksey, Iacoangeli, Alfredo, van Rheenen, Wouter, van den Berg, Leonard H., Shaw, Pamela J., Shaw, Cristopher E., Morrison, Karen E., Al-Chalabi, Ammar, Veldink, Jan H., Hannon, Eilis, Mill, Jonathan, Wray, Naomi R., McRae, Allan F., the Alzheimer's Disease Neuroimaging Initiative, and the Australian Imaging Biomarkers and Lifestyle study

Abstract

Background: People with neurodegenerative disorders show diverse clinical syndromes, genetic heterogeneity, and distinct brain pathological changes, but studies report overlap between these features. DNA methylation (DNAm) provides a way to explore this overlap and heterogeneity as it is determined by the combined effects of genetic variation and the environment. In this study, we aim to identify shared blood DNAm differences between controls and people with Alzheimer’s disease, amyotrophic lateral sclerosis, and Parkinson’s disease. Results: We use a mixed-linear model method (MOMENT) that accounts for the effect of (un)known confounders, to test for the association of each DNAm site with each disorder. While only three probes are found to be genome-wide significant in each MOMENT association analysis of amyotrophic lateral sclerosis and Parkinson’s disease (and none with Alzheimer’s disease), a fixed-effects meta-analysis of the three disorders results in 12 genome-wide significant differentially methylated positions. Predicted immune cell-type proportions are disrupted across all neurodegenerative disorders. Protein inflammatory markers are correlated with profile sum-scores derived from disease-associated immune cell-type proportions in a healthy aging cohort. In contrast, they are not correlated with MOMENT DNAm-derived profile sum-scores, calculated using effect sizes of the 12 differentially methylated positions as weights. Conclusions: We identify shared differentially methylated positions in whole blood between neurodegenerative disorders that point to shared pathogenic mechanisms. These shared differentially methylated positions may reflect causes or consequences of disease, but they are unlikely to reflect cell-type proportion differences.

Published
2021

3. Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders

Author

<p>Funding information : https://genomebiology.biomedcentral.com/articles/10.1186/s13059-021-02275-5 National Health and Medical Research Council Australian Research Council Edith Cowan University</p>, Nabais, Marta F., Laws, Simon M., Lin, Tian, Vallerga, Costanza L., Armstrong, Nicola J., Blair, Ian P., Kwok, John B., Mather, Karen A., Mellick, George D., Sachdev, Perminder S., Wallace, Leanne, Henders, Anjali K., Zwamborn, Ramona A. J., Hop, Paul J., Lunnon, Katie, Pishva, Ehsan, Roubroeks, Janou A. Y., Soininen, Hilkka, Tsolaki, Magda, Mecocci, Patrizia, Lovestone, Simon, Kłoszewska, Iwona, Vellas, Bruno, Furlong, Sarah, Garton, Fleur C., Henderson, Robert D., Mathers, Susan, McCombe, Pamela A., Needham, Merrilee, Ngo, Shyuan T., Nicholson, Garth, Pamphlett, Roger, Rowe, Dominic B., Steyn, Frederik J., Williams, Kelly L., Anderson, Tim J., Bentley, Steven R., Dalrymple-Alford, John, Fowder, Javed, Gratten, Jacob, Halliday, Glenda, Hickie, Ian B., Kennedy, Martin, Lewis, Simon J. G., Montgomery, Grant W., Pearson, John, Pitcher, Toni L., Silburn, Peter, Zhang, Futao, Visscher, Peter M., Yang, Jian, Stevenson, Anna J., Hillary, Robert F., Marioni, Riccardo E., Harris, Sarah E., Deary, Ian J., Jones, Ashley R., Shatunov, Aleksey, Iacoangeli, Alfredo, van Rheenen, Wouter, van den Berg, Leonard H., Shaw, Pamela J., Shaw, Cristopher E., Morrison, Karen E., Al-Chalabi, Ammar, Veldink, Jan H., Hannon, Eilis, Mill, Jonathan, Wray, Naomi R., McRae, Allan F., the Alzheimer's Disease Neuroimaging Initiative, the Australian Imaging Biomarkers and Lifestyle study, <p>Funding information : https://genomebiology.biomedcentral.com/articles/10.1186/s13059-021-02275-5 National Health and Medical Research Council Australian Research Council Edith Cowan University</p>, Nabais, Marta F., Laws, Simon M., Lin, Tian, Vallerga, Costanza L., Armstrong, Nicola J., Blair, Ian P., Kwok, John B., Mather, Karen A., Mellick, George D., Sachdev, Perminder S., Wallace, Leanne, Henders, Anjali K., Zwamborn, Ramona A. J., Hop, Paul J., Lunnon, Katie, Pishva, Ehsan, Roubroeks, Janou A. Y., Soininen, Hilkka, Tsolaki, Magda, Mecocci, Patrizia, Lovestone, Simon, Kłoszewska, Iwona, Vellas, Bruno, Furlong, Sarah, Garton, Fleur C., Henderson, Robert D., Mathers, Susan, McCombe, Pamela A., Needham, Merrilee, Ngo, Shyuan T., Nicholson, Garth, Pamphlett, Roger, Rowe, Dominic B., Steyn, Frederik J., Williams, Kelly L., Anderson, Tim J., Bentley, Steven R., Dalrymple-Alford, John, Fowder, Javed, Gratten, Jacob, Halliday, Glenda, Hickie, Ian B., Kennedy, Martin, Lewis, Simon J. G., Montgomery, Grant W., Pearson, John, Pitcher, Toni L., Silburn, Peter, Zhang, Futao, Visscher, Peter M., Yang, Jian, Stevenson, Anna J., Hillary, Robert F., Marioni, Riccardo E., Harris, Sarah E., Deary, Ian J., Jones, Ashley R., Shatunov, Aleksey, Iacoangeli, Alfredo, van Rheenen, Wouter, van den Berg, Leonard H., Shaw, Pamela J., Shaw, Cristopher E., Morrison, Karen E., Al-Chalabi, Ammar, Veldink, Jan H., Hannon, Eilis, Mill, Jonathan, Wray, Naomi R., McRae, Allan F., the Alzheimer's Disease Neuroimaging Initiative, and the Australian Imaging Biomarkers and Lifestyle study

Abstract

Nabais, M. F., Laws, S. M., Lin, T., Vallerga, C. L., Armstrong, N. J., Blair, I. P., ... McRae, A. F. (2021). Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders. Genome Biology, 22, article 90. https://doi.org/10.1186/s13059-021-02275-5

4. Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders.

Author

Nabais MF, Laws SM, Lin T, Vallerga CL, Armstrong NJ, Blair IP, Kwok JB, Mather KA, Mellick GD, Sachdev PS, Wallace L, Henders AK, Zwamborn RAJ, Hop PJ, Lunnon K, Pishva E, Roubroeks JAY, Soininen H, Tsolaki M, Mecocci P, Lovestone S, Kłoszewska I, Vellas B, Furlong S, Garton FC, Henderson RD, Mathers S, McCombe PA, Needham M, Ngo ST, Nicholson G, Pamphlett R, Rowe DB, Steyn FJ, Williams KL, Anderson TJ, Bentley SR, Dalrymple-Alford J, Fowder J, Gratten J, Halliday G, Hickie IB, Kennedy M, Lewis SJG, Montgomery GW, Pearson J, Pitcher TL, Silburn P, Zhang F, Visscher PM, Yang J, Stevenson AJ, Hillary RF, Marioni RE, Harris SE, Deary IJ, Jones AR, Shatunov A, Iacoangeli A, van Rheenen W, van den Berg LH, Shaw PJ, Shaw CE, Morrison KE, Al-Chalabi A, Veldink JH, Hannon E, Mill J, Wray NR, and McRae AF

Subjects
Alleles, Biomarkers, Blood Cells metabolism, Case-Control Studies, Disease Susceptibility, Gene Expression Profiling, Genetic Loci, Genetic Predisposition to Disease, Humans, Neurodegenerative Diseases metabolism, DNA Methylation, Epigenesis, Genetic, Genome-Wide Association Study, Neurodegenerative Diseases etiology
Abstract

Background: People with neurodegenerative disorders show diverse clinical syndromes, genetic heterogeneity, and distinct brain pathological changes, but studies report overlap between these features. DNA methylation (DNAm) provides a way to explore this overlap and heterogeneity as it is determined by the combined effects of genetic variation and the environment. In this study, we aim to identify shared blood DNAm differences between controls and people with Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease., Results: We use a mixed-linear model method (MOMENT) that accounts for the effect of (un)known confounders, to test for the association of each DNAm site with each disorder. While only three probes are found to be genome-wide significant in each MOMENT association analysis of amyotrophic lateral sclerosis and Parkinson's disease (and none with Alzheimer's disease), a fixed-effects meta-analysis of the three disorders results in 12 genome-wide significant differentially methylated positions. Predicted immune cell-type proportions are disrupted across all neurodegenerative disorders. Protein inflammatory markers are correlated with profile sum-scores derived from disease-associated immune cell-type proportions in a healthy aging cohort. In contrast, they are not correlated with MOMENT DNAm-derived profile sum-scores, calculated using effect sizes of the 12 differentially methylated positions as weights., Conclusions: We identify shared differentially methylated positions in whole blood between neurodegenerative disorders that point to shared pathogenic mechanisms. These shared differentially methylated positions may reflect causes or consequences of disease, but they are unlikely to reflect cell-type proportion differences.

Published
2021
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