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1. Erratum: GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium

Author: Trampush, JW, Yang, MLZ, Yu, J, Knowles, E, Davies, G, Liewald, DC, Starr, JM, Djurovic, S, Melle, I, Sundet, K, Christoforou, A, Reinvang, I, DeRosse, P, Lundervold, AJ, Steen, VM, Espeseth, T, Räikkönen, K, Widen, E, Palotie, A, Eriksson, JG, Giegling, I, Konte, B, Roussos, P, Giakoumaki, S, Burdick, KE, Payton, A, Ollier, W, Horan, M, Chiba-Falek, O, Attix, DK, Need, AC, Cirulli, ET, Voineskos, AN, Stefanis, NC, Avramopoulos, D, Hatzimanolis, A, Arking, DE, Smyrnis, N, Bilder, RM, Freimer, NA, Cannon, TD, London, E, Poldrack, RA, Sabb, FW, Congdon, E, Conley, ED, Scult, MA, Dickinson, D, Straub, RE, Donohoe, G, Morris, D, Corvin, A, Gill, M, Hariri, AR, Weinberger, DR, Pendleton, N, Bitsios, P, Rujescu, D, Lahti, J, Le Hellard, S, Keller, MC, Andreassen, OA, Deary, IJ, Glahn, DC, Malhotra, AK, and Lencz, T
Subjects: Biomedical and Clinical Sciences, Biological Psychology, Clinical and Health Psychology, Clinical Sciences, Psychology, Genetics, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Biological psychology, Clinical and health psychology
Abstract: This corrects the article DOI: 10.1038/mp.2016.244.
Published: 2017

2. GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.

Author: Trampush, JW, Yang, MLZ, Yu, J, Knowles, E, Davies, G, Liewald, DC, Starr, JM, Djurovic, S, Melle, I, Sundet, K, Christoforou, A, Reinvang, I, DeRosse, P, Lundervold, AJ, Steen, VM, Espeseth, T, Räikkönen, K, Widen, E, Palotie, A, Eriksson, JG, Giegling, I, Konte, B, Roussos, P, Giakoumaki, S, Burdick, KE, Payton, A, Ollier, W, Horan, M, Chiba-Falek, O, Attix, DK, Need, AC, Cirulli, ET, Voineskos, AN, Stefanis, NC, Avramopoulos, D, Hatzimanolis, A, Arking, DE, Smyrnis, N, Bilder, RM, Freimer, NA, Cannon, TD, London, E, Poldrack, RA, Sabb, FW, Congdon, E, Conley, ED, Scult, MA, Dickinson, D, Straub, RE, Donohoe, G, Morris, D, Corvin, A, Gill, M, Hariri, AR, Weinberger, DR, Pendleton, N, Bitsios, P, Rujescu, D, Lahti, J, Le Hellard, S, Keller, MC, Andreassen, OA, Deary, IJ, Glahn, DC, Malhotra, AK, and Lencz, T
Subjects: Psychiatry, Medical and Health Sciences, Biological Sciences, Psychology and Cognitive Sciences
Abstract: This corrects the article DOI: 10.1038/mp.2016.244.
Published: 2017

3. A Pregnancy and Childhood Epigenetics Consortium (PACE) meta-analysis highlights potential relationships between birth order and neonatal blood DNA methylation

Author: Li, S., Spitz, N., Ghantous, A., Abrishamcar, S., Reimann, B., Marques, I., Silver, M.J., Aguilar-Lacasaña, S., Kitaba, N., Rezwan, F.I., Röder, Stefan, Sirignano, L., Tuhkanen, J., Mancano, G., Sharp, G.C., Metayer, C., Morimoto, L., Stein, D.J., Zar, H.J., Alfano, R., Nawrot, T., Wang, C., Kajantie, E., Keikkala, E., Mustaniemi, S., Ronkainen, J., Sebert, S., Silva, W., Vääräsmäki, M., Jaddoe, V.W.V., Bernstein, R.M., Prentice, A.M., Cosin-Tomas, M., Dwyer, T., Håberg, S.E., Herceg, Z., Magnus, M.C., Munthe-Kaas, M.C., Page, C.M., Völker, M., Gilles, M., Send, T., Witt, S., Zillich, L., Gagliardi, L., Richiardi, L., Czamara, D., Räikkönen, K., Chatzi, L., Vafeiadi, M., Arshad, S.H., Ewart, S, Plusquin, M., Felix, J.F., Moore, S.E., Vrijheid, M., Holloway, J.W., Karmaus, W., Herberth, Gunda, Zenclussen, Ana Claudia, Streit, F., Lahti, J., Hüls, A., Hoang, T.T., London, S.J., Wiemels, J.L., Li, S., Spitz, N., Ghantous, A., Abrishamcar, S., Reimann, B., Marques, I., Silver, M.J., Aguilar-Lacasaña, S., Kitaba, N., Rezwan, F.I., Röder, Stefan, Sirignano, L., Tuhkanen, J., Mancano, G., Sharp, G.C., Metayer, C., Morimoto, L., Stein, D.J., Zar, H.J., Alfano, R., Nawrot, T., Wang, C., Kajantie, E., Keikkala, E., Mustaniemi, S., Ronkainen, J., Sebert, S., Silva, W., Vääräsmäki, M., Jaddoe, V.W.V., Bernstein, R.M., Prentice, A.M., Cosin-Tomas, M., Dwyer, T., Håberg, S.E., Herceg, Z., Magnus, M.C., Munthe-Kaas, M.C., Page, C.M., Völker, M., Gilles, M., Send, T., Witt, S., Zillich, L., Gagliardi, L., Richiardi, L., Czamara, D., Räikkönen, K., Chatzi, L., Vafeiadi, M., Arshad, S.H., Ewart, S, Plusquin, M., Felix, J.F., Moore, S.E., Vrijheid, M., Holloway, J.W., Karmaus, W., Herberth, Gunda, Zenclussen, Ana Claudia, Streit, F., Lahti, J., Hüls, A., Hoang, T.T., London, S.J., and Wiemels, J.L.
Abstract: Higher birth order is associated with altered risk of many disease states. Changes in placentation and exposures to in utero growth factors with successive pregnancies may impact later life disease risk via persistent DNA methylation alterations. We investigated birth order with Illumina DNA methylation array data in each of 16 birth cohorts (8164 newborns) with European, African, and Latino ancestries from the Pregnancy and Childhood Epigenetics Consortium. Meta-analyzed data demonstrated systematic DNA methylation variation in 341 CpGs (FDR adjusted P < 0.05) and 1107 regions. Forty CpGs were located within known quantitative trait loci for gene expression traits in blood, and trait enrichment analysis suggested a strong association with immune-related, transcriptional control, and blood pressure regulation phenotypes. Decreasing fertility rates worldwide with the concomitant increased proportion of first-born children highlights a potential reflection of birth order-related epigenomic states on changing disease incidence trends.
Published: 2024

4. Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications

Author: Sterenborg, R.B.T.M., Steinbrenner, I., Li, Yong, Bujnis, M.N., Naito, T., Marouli, E., Galesloot, T.E., Babajide, O., Andreasen, L., Astrup, A., Åsvold, B.O., Bandinelli, S., Beekman, M., Beilby, J.P., Bork-Jensen, J., Boutin, T., Brody, J.A., Brown, S.J., Brumpton, B., Campbell, P.J., Cappola, A.R., Ceresini, G., Chaker, L., Chasman, D.I., Concas, M.P., Coutinho de Almeida, Rodrigo, Cross, S.M., Cucca, F., Deary, I.J., Kjaergaard, A.D., Echouffo Tcheugui, J.B., Ellervik, C., Eriksson, J.G., Ferrucci, L., Freudenberg, J., Fuchsberger, C., Gieger, C., Giulianini, F., Gögele, M., Graham, S.E., Grarup, N., Gunjača, I., Hansen, T., Harding, B.N., Harris, S.E., Haunsø, S., Hayward, C., Hui, J., Ittermann, T., Jukema, J.W., Kajantie, E., Kanters, J.K., Kårhus, L.L., Kiemeney, L.A.L.M., Kühnel, B., Lahti, J., Langenberg, C., Lapauw, B., Leese, G., Li, Shuo, Liewald, D.C.M., Linneberg, A., Lominchar, J.V.T., Luan, Jian'an, Martin, N.G., Matana, A., Meima, M.E., Meitinger, T., Meulenbelt, I., Mitchell, B.D., Møllehave, L.T., Mora, S., Naitza, S., Nauck, M., Netea-Maier, R.T., Noordam, R., Nursyifa, C., Okada, Y., Onano, S., Papadopoulou, A., Palmer, C.N.A., Pattaro, C., Pedersen, O., Peters, A., Pietzner, M., Polašek, O., Pramstaller, P.P., Psaty, B.M., Punda, A., Ray, D., Redmond, P., Richards, J.B., Ridker, P.M., Russ, T.C., Ryan, K.A., Olesen, M.S., Schultheiss, U.T., Selvin, E., Siddiqui, M.K., Teumer, A., Medici, M., Sterenborg, R.B.T.M., Steinbrenner, I., Li, Yong, Bujnis, M.N., Naito, T., Marouli, E., Galesloot, T.E., Babajide, O., Andreasen, L., Astrup, A., Åsvold, B.O., Bandinelli, S., Beekman, M., Beilby, J.P., Bork-Jensen, J., Boutin, T., Brody, J.A., Brown, S.J., Brumpton, B., Campbell, P.J., Cappola, A.R., Ceresini, G., Chaker, L., Chasman, D.I., Concas, M.P., Coutinho de Almeida, Rodrigo, Cross, S.M., Cucca, F., Deary, I.J., Kjaergaard, A.D., Echouffo Tcheugui, J.B., Ellervik, C., Eriksson, J.G., Ferrucci, L., Freudenberg, J., Fuchsberger, C., Gieger, C., Giulianini, F., Gögele, M., Graham, S.E., Grarup, N., Gunjača, I., Hansen, T., Harding, B.N., Harris, S.E., Haunsø, S., Hayward, C., Hui, J., Ittermann, T., Jukema, J.W., Kajantie, E., Kanters, J.K., Kårhus, L.L., Kiemeney, L.A.L.M., Kühnel, B., Lahti, J., Langenberg, C., Lapauw, B., Leese, G., Li, Shuo, Liewald, D.C.M., Linneberg, A., Lominchar, J.V.T., Luan, Jian'an, Martin, N.G., Matana, A., Meima, M.E., Meitinger, T., Meulenbelt, I., Mitchell, B.D., Møllehave, L.T., Mora, S., Naitza, S., Nauck, M., Netea-Maier, R.T., Noordam, R., Nursyifa, C., Okada, Y., Onano, S., Papadopoulou, A., Palmer, C.N.A., Pattaro, C., Pedersen, O., Peters, A., Pietzner, M., Polašek, O., Pramstaller, P.P., Psaty, B.M., Punda, A., Ray, D., Redmond, P., Richards, J.B., Ridker, P.M., Russ, T.C., Ryan, K.A., Olesen, M.S., Schultheiss, U.T., Selvin, E., Siddiqui, M.K., Teumer, A., and Medici, M.
Abstract: Contains fulltext : 304858.pdf (Publisher’s version ) (Open Access), To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.
Published: 2024

5. GWAS for executive function and processing speed suggests involvement of the CADM2 gene

Author: Ibrahim-Verbaas, CA, Bressler, J, Debette, S, Schuur, M, Smith, AV, Bis, JC, Davies, G, Trompet, S, Smith, JA, Wolf, C, Chibnik, LB, Liu, Y, Vitart, V, Kirin, M, Petrovic, K, Polasek, O, Zgaga, L, Fawns-Ritchie, C, Hoffmann, P, Karjalainen, J, Lahti, J, Llewellyn, DJ, Schmidt, CO, Mather, KA, Chouraki, V, Sun, Q, Resnick, SM, Rose, LM, Oldmeadow, C, Stewart, M, Smith, BH, Gudnason, V, Yang, Q, Mirza, SS, Jukema, JW, deJager, PL, Harris, TB, Liewald, DC, Amin, N, Coker, LH, Stegle, O, Lopez, OL, Schmidt, R, Teumer, A, Ford, I, Karbalai, N, Becker, JT, Jonsdottir, MK, Au, R, Fehrmann, RSN, Herms, S, Nalls, M, Zhao, W, Turner, ST, Yaffe, K, Lohman, K, van Swieten, JC, Kardia, SLR, Knopman, DS, Meeks, WM, Heiss, G, Holliday, EG, Schofield, PW, Tanaka, T, Stott, DJ, Wang, J, Ridker, P, Gow, AJ, Pattie, A, Starr, JM, Hocking, LJ, Armstrong, NJ, McLachlan, S, Shulman, JM, Pilling, LC, Eiriksdottir, G, Scott, RJ, Kochan, NA, Palotie, A, Hsieh, Y-C, Eriksson, JG, Penman, A, Gottesman, RF, Oostra, BA, Yu, L, DeStefano, AL, Beiser, A, Garcia, M, Rotter, JI, Nöthen, MM, Hofman, A, Slagboom, PE, Westendorp, RGJ, Buckley, BM, Wolf, PA, Uitterlinden, AG, Psaty, BM, Grabe, HJ, Bandinelli, S, and Chasman, DI
Subjects: Biological Psychology, Clinical and Health Psychology, Psychology, Human Genome, Neurosciences, Genetics, Clinical Research, Aging, Aetiology, 2.1 Biological and endogenous factors, Aged, Aged, 80 and over, Cell Adhesion Molecules, Cognition, Cohort Studies, Executive Function, Female, Genetic Association Studies, Genetic Variation, Genome-Wide Association Study, Genomics, Humans, Introns, Male, Middle Aged, Neuropsychological Tests, Polymorphism, Single Nucleotide, White People, gamma-Aminobutyric Acid, Generation Scotland, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Biological psychology, Clinical and health psychology
Abstract: To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32,070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.
Published: 2016

6. Novel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study

Author: Gottlieb, DJ, Hek, K, Chen, T-H, Watson, NF, Eiriksdottir, G, Byrne, EM, Cornelis, M, Warby, SC, Bandinelli, S, Cherkas, L, Evans, DS, Grabe, HJ, Lahti, J, Li, M, Lehtimäki, T, Lumley, T, Marciante, KD, Pérusse, L, Psaty, BM, Robbins, J, Tranah, GJ, Vink, JM, Wilk, JB, Stafford, JM, Bellis, C, Biffar, R, Bouchard, C, Cade, B, Curhan, GC, Eriksson, JG, Ewert, R, Ferrucci, L, Fülöp, T, Gehrman, PR, Goodloe, R, Harris, TB, Heath, AC, Hernandez, D, Hofman, A, Hottenga, J-J, Hunter, DJ, Jensen, MK, Johnson, AD, Kähönen, M, Kao, L, Kraft, P, Larkin, EK, Lauderdale, DS, Luik, AI, Medici, M, Montgomery, GW, Palotie, A, Patel, SR, Pistis, G, Porcu, E, Quaye, L, Raitakari, O, Redline, S, Rimm, EB, Rotter, JI, Smith, AV, Spector, TD, Teumer, A, Uitterlinden, AG, Vohl, M-C, Widen, E, Willemsen, G, Young, T, Zhang, X, Liu, Y, Blangero, J, Boomsma, DI, Gudnason, V, Hu, F, Mangino, M, Martin, NG, O'Connor, GT, Stone, KL, Tanaka, T, Viikari, J, Gharib, SA, Punjabi, NM, Räikkönen, K, Völzke, H, Mignot, E, and Tiemeier, H
Subjects: Biomedical and Clinical Sciences, Clinical Sciences, Mental Health, Sleep Research, Clinical Research, Brain Disorders, Genetics, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Adult, Black or African American, Aged, Dyssomnias, Female, Genetic Association Studies, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Self Report, Sleep, White People, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Biological psychology, Clinical and health psychology
Abstract: Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study (GWAS) of usual sleep duration was conducted using 18 population-based cohorts totaling 47 180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35- to 80-kb upstream from the thyroid-specific transcription factor PAX8 (lowest P=1.1 × 10(-9)). This finding was replicated in an African-American sample of 4771 individuals (lowest P=9.3 × 10(-4)). The strongest combined association was at rs1823125 (P=1.5 × 10(-10), minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 min longer per night. The alleles associated with longer sleep duration were associated in previous GWAS with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.
Published: 2015

7. Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949).

Author: Davies, G, Armstrong, N, Bis, JC, Bressler, J, Chouraki, V, Giddaluru, S, Hofer, E, Ibrahim-Verbaas, CA, Kirin, M, Lahti, J, van der Lee, SJ, Le Hellard, S, Liu, T, Marioni, RE, Oldmeadow, C, Postmus, I, Smith, AV, Smith, JA, Thalamuthu, A, Thomson, R, Vitart, V, Wang, J, Yu, L, Zgaga, L, Zhao, W, Boxall, R, Harris, SE, Hill, WD, Liewald, DC, Luciano, M, Adams, H, Ames, D, Amin, N, Amouyel, P, Assareh, AA, Au, R, Becker, JT, Beiser, A, Berr, C, Bertram, L, Boerwinkle, E, Buckley, BM, Campbell, H, Corley, J, De Jager, PL, Dufouil, C, Eriksson, JG, Espeseth, T, Faul, JD, Ford, I, Generation Scotland, Gottesman, RF, Griswold, ME, Gudnason, V, Harris, TB, Heiss, G, Hofman, A, Holliday, EG, Huffman, J, Kardia, SLR, Kochan, N, Knopman, DS, Kwok, JB, Lambert, J-C, Lee, T, Li, G, Li, S-C, Loitfelder, M, Lopez, OL, Lundervold, AJ, Lundqvist, A, Mather, KA, Mirza, SS, Nyberg, L, Oostra, BA, Palotie, A, Papenberg, G, Pattie, A, Petrovic, K, Polasek, O, Psaty, BM, Redmond, P, Reppermund, S, Rotter, JI, Schmidt, H, Schuur, M, Schofield, PW, Scott, RJ, Steen, VM, Stott, DJ, van Swieten, JC, Taylor, KD, Trollor, J, Trompet, S, Uitterlinden, AG, Weinstein, G, Widen, E, Windham, BG, Jukema, JW, and Wright, AF
Subjects: Generation Scotland, Humans, Genetic Predisposition to Disease, HMGN1 Protein, Cohort Studies, Cognition, Cognition Disorders, Neuropsychological Tests, Phenotype, Polymorphism, Single Nucleotide, Aged, Aged, 80 and over, Middle Aged, Scotland, Female, Male, Atherosclerosis, Genome-Wide Association Study, and over, Polymorphism, Single Nucleotide, Psychiatry, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences
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.
Published: 2015

8. Work ability trends 2000-2020 and projections until 2040 in Finland

Author: Lahti, J, primary, Reinikainen, J, additional, Kontto, J, additional, Zhi, Z, additional, Koskinen, S, additional, Laaksonen, M, additional, Partonen, T, additional, Elonheimo, H, additional, Lundqvist, A, additional, and Tolonen, H, additional
Published: 2023
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9. Joint trajectories of physical activity, self-rated health and income in Finnish statutory retirees

Author: Lallukka, T, primary, Kolmonen, P, additional, Rahkonen, O, additional, Lahelma, E, additional, and Lahti, J, additional
Published: 2023
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10. Joint associations of leisure time physical activity and sitting time with sickness absence

Author: Sarttila, K, primary, Pohjola, V, additional, Kuusela, M, additional, Hautala, A, additional, Lahti, J, additional, and Lundqvist, A, additional
Published: 2023
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11. A genome-wide meta-analysis of association studies of Cloninger's Temperament Scales.

Author: Service, SK, Verweij, KJH, Lahti, J, Congdon, E, Ekelund, J, Hintsanen, M, Räikkönen, K, Lehtimäki, T, Kähönen, M, Widen, E, Taanila, A, Veijola, J, Heath, AC, Madden, PAF, Montgomery, GW, Sabatti, C, Järvelin, M-R, Palotie, A, Raitakari, O, Viikari, J, Martin, NG, Eriksson, JG, Keltikangas-Järvinen, L, Wray, NR, and Freimer, NB
Subjects: Humans, Cohort Studies, Longitudinal Studies, Reproducibility of Results, Personality, Temperament, Personality Inventory, Psychometrics, Twins, Genotype, Linkage Disequilibrium, Phenotype, Genetic Heterogeneity, Polymorphism, Single Nucleotide, Adult, Middle Aged, Australia, Finland, Female, Male, Genome-Wide Association Study, association, genetics, genome-wide, meta-analysis, personality, temperament, Polymorphism, Single Nucleotide, Clinical Sciences, Public Health and Health Services, Psychology
Abstract: Temperament has a strongly heritable component, yet multiple independent genome-wide studies have failed to identify significant genetic associations. We have assembled the largest sample to date of persons with genome-wide genotype data, who have been assessed with Cloninger's Temperament and Character Inventory. Sum scores for novelty seeking, harm avoidance, reward dependence and persistence have been measured in over 11,000 persons collected in four different cohorts. Our study had >80% power to identify genome-wide significant loci (P
Published: 2012

12. Positive maternal mental health during pregnancy and mental and behavioral disorders in children:a prospective pregnancy cohort study

Author: Lähdepuro, A. (Anna), Lahti-Pulkkinen, M. (Marius), Pyhälä, R. (Riikka), Tuovinen, S. (Soile), Lahti, J. (Jari), Heinonen, K. (Kati), Laivuori, H. (Hannele), Villa, P. M. (Pia M.), Reynolds, R. M. (Rebecca M.), Kajantie, E. (Eero), Girchenko, P. (Polina), Räikkönen, K. (Katri), Lähdepuro, A. (Anna), Lahti-Pulkkinen, M. (Marius), Pyhälä, R. (Riikka), Tuovinen, S. (Soile), Lahti, J. (Jari), Heinonen, K. (Kati), Laivuori, H. (Hannele), Villa, P. M. (Pia M.), Reynolds, R. M. (Rebecca M.), Kajantie, E. (Eero), Girchenko, P. (Polina), and Räikkönen, K. (Katri)
Abstract: Background: The role of positive maternal mental health during pregnancy in child mental health remains largely unknown. We investigated whether positive maternal mental health during pregnancy is associated with lower hazards of mental and behavioral disorders in children and mitigates the adverse effects of negative maternal mental health. Methods: Among 3,378 mother–child dyads of the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction study, mothers reported their positive mental health biweekly throughout pregnancy with the Positive and Negative Affect Schedule, the Spielberger State Anxiety Inventory Curiosity scale, and a visual analogue scale for social support, and negative mental health with the Center for Epidemiologic Studies Depression Scale. We extracted data on their mental and behavioral disorder diagnoses from a nationwide medical register. This register provided data on their children’s mental and behavioral disorder diagnoses as well, from birth until 8.4−12.8 (Median = 10.2, Interquartile Range 9.7−10.8) years of age. Results: A positive maternal mental health composite score during pregnancy was associated with a lower hazard of any mental and behavioral disorder among all children [Hazard Ratio (HR) = 0.79, 95% Confidence Interval (CI) 0.71 − 0.87] and among children of mothers experiencing clinically relevant depressive symptoms during pregnancy [HR = 0.80, 95%CI 0.64 − 1.00] and/or mental and behavioral disorders before or during pregnancy [HR = 0.69, 95%CI 0.55−0.86]. These associations were independent of covariates. Conclusions: Children whose mothers had more positive mental health during pregnancy were less likely to develop mental and behavioral disorders. Protective effects were seen also among children of mothers facing mental health adversities before or during pregnancy.
Published: 2023

13. Genetic insights into resting heart rate and its role in cardiovascular disease.

Author: Vegte, Y.J. van de, Eppinga, R.N., Ende, M.Y. van der, Hagemeijer, Y.P., Mahendran, Y., Salfati, E., Smith, A.V., Tan, V.Y., Arking, D.E., Ntalla, I., Appel, E.V., Schurmann, C., Brody, J.A., Rueedi, R., Polasek, O., Sveinbjornsson, G., Lecoeur, C., Ladenvall, C., Zhao, J.H., Isaacs, A., Wang, L., Luan, Jian'an, Hwang, S.J., Mononen, N., Auro, K., Jackson, A.U., Bielak, L.F., Zeng, L., Shah, N., Nethander, M., Campbell, A., Rankinen, T., Pechlivanis, S., Qi, L., Zhao, Wei, Rizzi, F., Tanaka, T., Robino, A., Cocca, M., Lange, L., Müller-Nurasyid, M., Roselli, C., Zhang, W, Kleber, M.E., Guo, X., Lin, H.J., Pavani, F., Galesloot, T.E., Noordam, R., Milaneschi, Y., Schraut, K.E., Hoed, M. den, Degenhardt, F., Trompet, S., Berg, M.E. van den, Pistis, G., Tham, Y.C., Weiss, S., Sim, X.S., Li, H.L., Most, P.J. van der, Nolte, I.M., Lyytikäinen, L.P., Said, M.A., Witte, D.R., Iribarren, C., Launer, L., Ring, S.M., Vries, P.S. de, Sever, P., Linneberg, A., Bottinger, E.P., Padmanabhan, S., Psaty, B.M., Sotoodehnia, N., Kolcic, I., Arnar, D.O., Gudbjartsson, D.F., Holm, H., Balkau, B., Silva, C.T., Newton-Cheh, C.H., Nikus, K., Salo, P., Mohlke, K.L., Peyser, P.A., Schunkert, H., Lorentzon, M., Lahti, J., Rao, D.C., Cornelis, M.C., Faul, J.D., Smith, J.A., Stolarz-Skrzypek, K., Bandinelli, S., Concas, M.P., Sinagra, G., Meitinger, T., Waldenberger, M., Sinner, M.F., Strauch, K., Delgado, G.E., Taylor, K.D., Yao, J., Foco, L., Melander, O., Graaf, J. de, Mutsert, R. de, Geus, E.J.C. de, Johansson, Å., Joshi, P.K., Lind, L., Franke, A., Macfarlane, P.W., Tarasov, K.V., Tan, N., Felix, S.B., Tai, E.S., Quek, D.Q., Snieder, H., Ormel, J., Ingelsson, M., Lindgren, C., Morris, A.P., Raitakari, O.T., Hansen, T., Assimes, T., Gudnason, V., Timpson, N.J., Morrison, A.C., Munroe, P.B., Strachan, D.P., Grarup, N., Loos, R.J.F., Heckbert, S.R., Vollenweider, P., Hayward, C., Stefansson, K., Froguel, P., Groop, L., Wareham, N.J., Duijn, C.M. van, Feitosa, M.F., O'Donnell, C.J., Kähönen, M., Perola, M., Boehnke, M., Kardia, S.L.R., Erdmann, J., Palmer, C.N.A., Ohlsson, C., Porteous, D.J., Eriksson, J.G., Bouchard, C., Moebus, S., Kraft, P., Weir, D.R., Cusi, D., Ferrucci, L., Ulivi, S., Girotto, G., Correa, A., Kääb, S., Peters, A., Chambers, J.C., Kooner, J.S., März, W., Rotter, J.I., Hicks, A.A., Smith, J.G., Kiemeney, L.A.L.M., Mook-Kanamori, D.O., Penninx, B.W.J.H., Gyllensten, U., Wilson, J.F., Burgess, S., Sundström, J., Lieb, W., Jukema, J.W., Eijgelsheim, M., Lakatta, E.L.M., Cheng, C.Y., Dörr, M., Wong, T.Y., Sabanayagam, C., Oldehinkel, A.J., Riese, H., Lehtimäki, T., Verweij, N., Harst, P. van der, Vegte, Y.J. van de, Eppinga, R.N., Ende, M.Y. van der, Hagemeijer, Y.P., Mahendran, Y., Salfati, E., Smith, A.V., Tan, V.Y., Arking, D.E., Ntalla, I., Appel, E.V., Schurmann, C., Brody, J.A., Rueedi, R., Polasek, O., Sveinbjornsson, G., Lecoeur, C., Ladenvall, C., Zhao, J.H., Isaacs, A., Wang, L., Luan, Jian'an, Hwang, S.J., Mononen, N., Auro, K., Jackson, A.U., Bielak, L.F., Zeng, L., Shah, N., Nethander, M., Campbell, A., Rankinen, T., Pechlivanis, S., Qi, L., Zhao, Wei, Rizzi, F., Tanaka, T., Robino, A., Cocca, M., Lange, L., Müller-Nurasyid, M., Roselli, C., Zhang, W, Kleber, M.E., Guo, X., Lin, H.J., Pavani, F., Galesloot, T.E., Noordam, R., Milaneschi, Y., Schraut, K.E., Hoed, M. den, Degenhardt, F., Trompet, S., Berg, M.E. van den, Pistis, G., Tham, Y.C., Weiss, S., Sim, X.S., Li, H.L., Most, P.J. van der, Nolte, I.M., Lyytikäinen, L.P., Said, M.A., Witte, D.R., Iribarren, C., Launer, L., Ring, S.M., Vries, P.S. de, Sever, P., Linneberg, A., Bottinger, E.P., Padmanabhan, S., Psaty, B.M., Sotoodehnia, N., Kolcic, I., Arnar, D.O., Gudbjartsson, D.F., Holm, H., Balkau, B., Silva, C.T., Newton-Cheh, C.H., Nikus, K., Salo, P., Mohlke, K.L., Peyser, P.A., Schunkert, H., Lorentzon, M., Lahti, J., Rao, D.C., Cornelis, M.C., Faul, J.D., Smith, J.A., Stolarz-Skrzypek, K., Bandinelli, S., Concas, M.P., Sinagra, G., Meitinger, T., Waldenberger, M., Sinner, M.F., Strauch, K., Delgado, G.E., Taylor, K.D., Yao, J., Foco, L., Melander, O., Graaf, J. de, Mutsert, R. de, Geus, E.J.C. de, Johansson, Å., Joshi, P.K., Lind, L., Franke, A., Macfarlane, P.W., Tarasov, K.V., Tan, N., Felix, S.B., Tai, E.S., Quek, D.Q., Snieder, H., Ormel, J., Ingelsson, M., Lindgren, C., Morris, A.P., Raitakari, O.T., Hansen, T., Assimes, T., Gudnason, V., Timpson, N.J., Morrison, A.C., Munroe, P.B., Strachan, D.P., Grarup, N., Loos, R.J.F., Heckbert, S.R., Vollenweider, P., Hayward, C., Stefansson, K., Froguel, P., Groop, L., Wareham, N.J., Duijn, C.M. van, Feitosa, M.F., O'Donnell, C.J., Kähönen, M., Perola, M., Boehnke, M., Kardia, S.L.R., Erdmann, J., Palmer, C.N.A., Ohlsson, C., Porteous, D.J., Eriksson, J.G., Bouchard, C., Moebus, S., Kraft, P., Weir, D.R., Cusi, D., Ferrucci, L., Ulivi, S., Girotto, G., Correa, A., Kääb, S., Peters, A., Chambers, J.C., Kooner, J.S., März, W., Rotter, J.I., Hicks, A.A., Smith, J.G., Kiemeney, L.A.L.M., Mook-Kanamori, D.O., Penninx, B.W.J.H., Gyllensten, U., Wilson, J.F., Burgess, S., Sundström, J., Lieb, W., Jukema, J.W., Eijgelsheim, M., Lakatta, E.L.M., Cheng, C.Y., Dörr, M., Wong, T.Y., Sabanayagam, C., Oldehinkel, A.J., Riese, H., Lehtimäki, T., Verweij, N., and Harst, P. van der
Abstract: Contains fulltext : 296013.pdf (Publisher’s version ) (Open Access), Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.
Published: 2023

14. Maternal exposure to childhood maltreatment and mental and behavioral disorders in children

Author: Airikka, A. (Aino), Lahti-Pulkkinen, M. (Marius), Tuovinen, S. (Soile), Heinonen, K. (Kati), Lahti, J. (Jari), Girchenko, P. (Polina), Lähdepuro, A. (Anna), Pyhälä, R. (Riikka), Czamara, D. (Darina), Villa, P. (Pia), Laivuori, H. (Hannele), Kajantie, E. (Eero), Binder, E. B. (Elisabeth B.), Räikkönen, K. (Katri), Airikka, A. (Aino), Lahti-Pulkkinen, M. (Marius), Tuovinen, S. (Soile), Heinonen, K. (Kati), Lahti, J. (Jari), Girchenko, P. (Polina), Lähdepuro, A. (Anna), Pyhälä, R. (Riikka), Czamara, D. (Darina), Villa, P. (Pia), Laivuori, H. (Hannele), Kajantie, E. (Eero), Binder, E. B. (Elisabeth B.), and Räikkönen, K. (Katri)
Abstract: Exposure to maltreatment in childhood is associated with lifelong risk of mental and behavioral disorders. Whether the effects extend to the next generation remains unclear. We examined whether maternal exposure to childhood abuse and neglect in her own childhood were associated with mental and behavioral disorders and psychiatric symptoms in her children, and whether maternal lifetime mental and behavioral disorders or lower education level mediated or added to the effects. Mothers (n = 2252) of the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction cohort study completed the Childhood Trauma Questionnaire and reported on their education and their 7.0–12.1-year-old children’s psychiatric symptoms using the Strengths and Difficulties Questionnaire. We identified lifetime mental and behavioral disorder diagnoses for the mothers and diagnoses for their children from birth (2006–2010) until 8.4–12.8 years (12/31/2018) from Care Register for Health Care. We found that maternal exposure to childhood abuse, but not neglect, was associated with higher hazards of mental and behavioral disorders (hazard ratio 1.20, 95% confidence interval 1.06–1.37) in children. These associations were partially mediated by maternal mental and behavioral disorders and education (proportion of effect size mediated: 23.8% and 15.1%, respectively), which together with maternal exposure to childhood abuse added to the hazard of mental and behavioral disorders in children. Similar associations were found for maternal exposure to childhood abuse and neglect with psychiatric symptoms in children. To conclude, maternal exposure to childhood maltreatment is associated with mental and behavioral disorders and psychiatric symptoms in children. Our findings call for interventions to prevent intergenerational transmission.
Published: 2023

15. Loci for insulin processing and secretion provide insight into type 2 diabetes risk

Author: Broadaway, K. A. (K. Alaine), Yin, X. (Xianyong), Williamson, A. (Alice), Parsons, V. A. (Victoria A.), Wilson, E. P. (Emma P.), Moxley, A. H. (Anne H.), Vadlamudi, S. (Swarooparani), Varshney, A. (Arushi), Jackson, A. U. (Anne U.), Ahuja, V. (Vasudha), Bornstein, S. R. (Stefan R.), Corbin, L. J. (Laura J.), Delgado, G. E. (Graciela E.), Dwivedi, O. P. (Om P.), Silva, L. F. (Lilian Fernandes), Frayling, T. M. (Timothy M.), Grallert, H. (Harald), Gustafsson, S. (Stefan), Hakaste, L. (Liisa), Hammar, U. (Ulf), Herder, C. (Christian), Herrmann, S. (Sandra), Hojlund, K. (Kurt), Hughes, D. A. (David A.), Kleber, M. E. (Marcus E.), Lindgren, C. M. (Cecilia M.), Liu, C.-T. (Ching-Ti), Luan, J. (Jian'an), Malmberg, A. (Anni), Moissl, A. P. (Angela P.), Morris, A. P. (Andrew P.), Perakakis, N. (Nikolaos), Peters, A. (Annette), Petrie, J. R. (John R.), Roden, M. (Michael), Schwarz, P. E. (Peter E. H.), Sharma, S. (Sapna), Silveira, A. (Angela), Strawbridge, R. J. (Rona J.), Tuomi, T. (Tiinamaija), Wood, A. R. (Andrew R.), Wu, P. (Peitao), Zethelius, B. (Bjorn), Baldassarre, D. (Damiano), Eriksson, J. G. (Johan G.), Fall, T. (Tove), Florez, J. C. (Jose C.), Fritsche, A. (Andreas), Gigante, B. (Bruna), Hamsten, A. (Anders), Kajantie, E. (Eero), Laakso, M. (Markku), Lahti, J. (Jari), Lawlor, D. A. (Deborah A.), Lind, L. (Lars), Maerz, W. (Winfried), Meigs, J. B. (James B.), Sundstrom, J. (Johan), Timpson, N. J. (Nicholas J.), Wagner, R. (Robert), Walker, M. (Mark), Wareham, N. J. (Nicholas J.), Watkins, H. (Hugh), Barroso, I. (Ines), O'Rahilly, S. (Stephen), Grarup, N. (Niels), Parker, S. C. (Stephen CJ.), Boehnke, M. (Michael), Langenberg, C. (Claudia), Wheeler, E. (Eleanor), Mohlke, K. L. (Karen L.), Broadaway, K. A. (K. Alaine), Yin, X. (Xianyong), Williamson, A. (Alice), Parsons, V. A. (Victoria A.), Wilson, E. P. (Emma P.), Moxley, A. H. (Anne H.), Vadlamudi, S. (Swarooparani), Varshney, A. (Arushi), Jackson, A. U. (Anne U.), Ahuja, V. (Vasudha), Bornstein, S. R. (Stefan R.), Corbin, L. J. (Laura J.), Delgado, G. E. (Graciela E.), Dwivedi, O. P. (Om P.), Silva, L. F. (Lilian Fernandes), Frayling, T. M. (Timothy M.), Grallert, H. (Harald), Gustafsson, S. (Stefan), Hakaste, L. (Liisa), Hammar, U. (Ulf), Herder, C. (Christian), Herrmann, S. (Sandra), Hojlund, K. (Kurt), Hughes, D. A. (David A.), Kleber, M. E. (Marcus E.), Lindgren, C. M. (Cecilia M.), Liu, C.-T. (Ching-Ti), Luan, J. (Jian'an), Malmberg, A. (Anni), Moissl, A. P. (Angela P.), Morris, A. P. (Andrew P.), Perakakis, N. (Nikolaos), Peters, A. (Annette), Petrie, J. R. (John R.), Roden, M. (Michael), Schwarz, P. E. (Peter E. H.), Sharma, S. (Sapna), Silveira, A. (Angela), Strawbridge, R. J. (Rona J.), Tuomi, T. (Tiinamaija), Wood, A. R. (Andrew R.), Wu, P. (Peitao), Zethelius, B. (Bjorn), Baldassarre, D. (Damiano), Eriksson, J. G. (Johan G.), Fall, T. (Tove), Florez, J. C. (Jose C.), Fritsche, A. (Andreas), Gigante, B. (Bruna), Hamsten, A. (Anders), Kajantie, E. (Eero), Laakso, M. (Markku), Lahti, J. (Jari), Lawlor, D. A. (Deborah A.), Lind, L. (Lars), Maerz, W. (Winfried), Meigs, J. B. (James B.), Sundstrom, J. (Johan), Timpson, N. J. (Nicholas J.), Wagner, R. (Robert), Walker, M. (Mark), Wareham, N. J. (Nicholas J.), Watkins, H. (Hugh), Barroso, I. (Ines), O'Rahilly, S. (Stephen), Grarup, N. (Niels), Parker, S. C. (Stephen CJ.), Boehnke, M. (Michael), Langenberg, C. (Claudia), Wheeler, E. (Eleanor), and Mohlke, K. L. (Karen L.)
Abstract: Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value <5×10⁻⁸), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher rather than lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait locus (eQTL) data, suggesting candidate genes, including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6‐3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal but not the islet NKX6‐3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms that may predispose one to disease.
Published: 2023

16. Maternal educational attainment in pregnancy and epigenome-wide DNA methylation changes in the offspring from birth until adolescence

Author: Choudhary, P., Monasso, G.S., Karhunen, V., Ronkainen, J., Mancano, G., Howe, C.G., Niu, Z., Zeng, X., Guan, W., Dou, J., Feinberg, J.I., Mordaunt, C., Pesce, G., Baïz, N., Alfano, R., Martens, D.S., Wang, C., Isaevska, E., Keikkala, E., Mustaniemi, S., Thio, C.H.L., Fraszczyk, E., Tobi, E.W., Starling, A.P., Cosin-Tomas, M., Urquiza, J., Röder, Stefan, Hoang, T.T., Page, C., Jima, D.D., House, J.S., Maguire, R.L., Ott, R., Pawlow, X., Sirignano, L., Zillich, L., Malmberg, A., Rauschert, S., Melton, P., Gong, T., Karlsson, R., Fore, R., Perng, W., Laubach, Z.M., Czamara, D., Sharp, G., Breton, C.V., Schisterman, E., Yeung, E., Mumford, S.L., Fallin, M.D., LaSalle, J.M., Schmidt, R.J., Bakulski, K.M., Annesi-Maesano, I., Heude, B., Nawrot, T.S., Plusquin, M., Ghantous, A., Herceg, Z., Nisticò, L., Vafeiadi, M., Kogevinas, M., Vääräsmäki, M., Kajantie, E., Snieder, H., Corpeleijn, E., Steegers-Theunissen, R.P.M., Yang, I.V., Dabelea, D., Fossati, S., Zenclussen, Ana Claudia, Herberth, Gunda, Magnus, M., Håberg, S.E., London, S.J., Munthe-Kaas, M.C., Murphy, S.K., Hoyo, C., Ziegler, A.-G., Hummel, S., Witt, S.H., Streit, F., Frank, J., Räikkönen, K., Lahti, J., Huang, R.-C., Almqvist, C., Hivert, M.-F., Jaddoe, V.W.V., Järvelin, M.-R., Kantomaa, M., Felix, J.F., Sebert, S., Choudhary, P., Monasso, G.S., Karhunen, V., Ronkainen, J., Mancano, G., Howe, C.G., Niu, Z., Zeng, X., Guan, W., Dou, J., Feinberg, J.I., Mordaunt, C., Pesce, G., Baïz, N., Alfano, R., Martens, D.S., Wang, C., Isaevska, E., Keikkala, E., Mustaniemi, S., Thio, C.H.L., Fraszczyk, E., Tobi, E.W., Starling, A.P., Cosin-Tomas, M., Urquiza, J., Röder, Stefan, Hoang, T.T., Page, C., Jima, D.D., House, J.S., Maguire, R.L., Ott, R., Pawlow, X., Sirignano, L., Zillich, L., Malmberg, A., Rauschert, S., Melton, P., Gong, T., Karlsson, R., Fore, R., Perng, W., Laubach, Z.M., Czamara, D., Sharp, G., Breton, C.V., Schisterman, E., Yeung, E., Mumford, S.L., Fallin, M.D., LaSalle, J.M., Schmidt, R.J., Bakulski, K.M., Annesi-Maesano, I., Heude, B., Nawrot, T.S., Plusquin, M., Ghantous, A., Herceg, Z., Nisticò, L., Vafeiadi, M., Kogevinas, M., Vääräsmäki, M., Kajantie, E., Snieder, H., Corpeleijn, E., Steegers-Theunissen, R.P.M., Yang, I.V., Dabelea, D., Fossati, S., Zenclussen, Ana Claudia, Herberth, Gunda, Magnus, M., Håberg, S.E., London, S.J., Munthe-Kaas, M.C., Murphy, S.K., Hoyo, C., Ziegler, A.-G., Hummel, S., Witt, S.H., Streit, F., Frank, J., Räikkönen, K., Lahti, J., Huang, R.-C., Almqvist, C., Hivert, M.-F., Jaddoe, V.W.V., Järvelin, M.-R., Kantomaa, M., Felix, J.F., and Sebert, S.
Abstract: Maternal educational attainment (MEA) shapes offspring health through multiple potential pathways. Differential DNA methylation may provide a mechanistic understanding of these long-term associations. We aimed to quantify the associations of MEA with offspring DNA methylation levels at birth, in childhood and in adolescence. Using 37 studies from high-income countries, we performed meta-analysis of epigenome-wide association studies (EWAS) to quantify the associations of completed years of MEA at the time of pregnancy with offspring DNA methylation levels at birth (n = 9 881), in childhood (n = 2 017), and adolescence (n = 2 740), adjusting for relevant covariates. MEA was found to be associated with DNA methylation at 473 cytosine-phosphate-guanine sites at birth, one in childhood, and four in adolescence. We observed enrichment for findings from previous EWAS on maternal folate, vitamin-B12 concentrations, maternal smoking, and pre-pregnancy BMI. The associations were directionally consistent with MEA being inversely associated with behaviours including smoking and BMI. Our findings form a bridge between socio-economic factors and biology and highlight potential pathways underlying effects of maternal education. The results broaden our understanding of bio-social associations linked to differential DNA methylation in multiple early stages of life. The data generated also offers an important resource to help a more precise understanding of the social determinants of health.
Published: 2023

17. Epigenome-wide meta-analysis of prenatal maternal stressful life events and newborn DNA methylation

Author: Kotsakis Ruehlmann, A., Sammallahti, S., Cortés Hidalgo, A.P., Bakulski, K.M., Binder, E.B., Campbell, M.L., Caramaschi, D., Cecil, C., Colicino, E., Cruceanu, C., Czamara, D., Dieckmann, L., Dou, J., Felix, J.F., Frank, J., Håberg, S.E., Herberth, Gunda, Hoang, T.T., Houtepen, L.C., Hüls, A., Koen, N., London, S.J., Magnus, M.C., Mancano, G., Mulder, R.H., Page, C.M., Räikkönen, K., Röder, Stefan, Schmidt, R.J., Send, T.S., Sharp, G., Stein, D.J., Streit, F., Tuhkanen, J., Witt, S.H., Zar, H.J., Zenclussen, Ana Claudia, Zhang, Y., Zillich, L., Wright, R., Lahti, J., Brunst, K.J., Kotsakis Ruehlmann, A., Sammallahti, S., Cortés Hidalgo, A.P., Bakulski, K.M., Binder, E.B., Campbell, M.L., Caramaschi, D., Cecil, C., Colicino, E., Cruceanu, C., Czamara, D., Dieckmann, L., Dou, J., Felix, J.F., Frank, J., Håberg, S.E., Herberth, Gunda, Hoang, T.T., Houtepen, L.C., Hüls, A., Koen, N., London, S.J., Magnus, M.C., Mancano, G., Mulder, R.H., Page, C.M., Räikkönen, K., Röder, Stefan, Schmidt, R.J., Send, T.S., Sharp, G., Stein, D.J., Streit, F., Tuhkanen, J., Witt, S.H., Zar, H.J., Zenclussen, Ana Claudia, Zhang, Y., Zillich, L., Wright, R., Lahti, J., and Brunst, K.J.
Abstract: Prenatal maternal stressful life events are associated with adverse neurodevelopmental outcomes in offspring. Biologic mechanisms underlying these associations are largely unknown, but DNA methylation likely plays a role. This meta-analysis included twelve datasets from ten pregnancy cohorts (N=5,496) within the international Pregnancy and Childhood Epigenetics consortium to examine maternal stressful life events during pregnancy and DNA methylation in cord blood. Children whose mothers reported higher levels of cumulative maternal stressful life events during pregnancy exhibited differential methylation of cg26579032 in ALKBH3. Stressor-specific domains of conflict with family/friends, abuse (physical, sexual, and emotional), and death of a close friend/relative were also associated with differential methylation of CpGs in APTX, MyD88, and both UHRF1 and SDCCAG8, respectively; these genes are implicated in neurodegeneration, immune and cellular functions, regulation of global methylation levels, metabolism, and schizophrenia risk. Thus, differences in DNA methylation at these loci may provide novel insights into potential mechanisms of neurodevelopment in offspring.
Published: 2023

18. Analysis of DNA methylation at birth and in childhood reveals changes associated with season of birth and latitude

Author: Kadalayil, L., Alam, M., White, C.H., Ghantous, A., Walton, E., Gruzieva, O., Merid, S.K., Kumar, A., Roy, R., Solomon, O., Huen, K., Eskenazi, B., Rzehak, P., Grote, V., Langhendries, J.-P., Verduci, E., Ferre, N., Gruszfeld, D., Gao, L., Guan, W., Zeng, X., Schisterman, E.F., Dou, J., Bakulski, K.M., Feinberg, J.I., Soomro, M.H., Pesce, G., Baiz, N., Isaevska, E., Plusquin, M., Vafeiadi, M., Roumeliotaki, T., Langie, S.A.S., Standaert, A., Allard, C., Perron, P., Bouchard, L., van Meel, E.R., Felix, J.F., Jaddoe, V.W.V., Yousefi, P.D., Ramlau‑Hansen, C.H., Relton, C.L., Tobi, E.W., Starling, A.P., Yang, I.V., Llambrich, M., Santorelli, G., Lepeule, J., Salas, L.A., Bustamante, M., Ewart, S.L., Zhang, H., Karmaus, W., Röder, Stefan, Zenclussen, Ana Claudia, Jin, J., Nystad, W., Page, C.M., Magnus, M., Jima, D.D., Hoyo, C., Maguire, R.L., Kvist, T., Czamara, D., Räikkönen, K., Gong, T., Ullemar, V., Rifas‐Shiman, S.L., Oken, E., Almqvist, C., Karlsson, R., Lahti, J., Murphy, S.K., Håberg, S.E., London, S., Herberth, Gunda, Arshad, H., Sunyer, J., Grazuleviciene, R., Dabelea, D., Steegers‑Theunissen, R.P.M., Nohr, E.A., Sørensen, T.I.A., Duijts, L., Hivert, M.-F., Nelen, V., Popovic, M., Kogevinas, M., Nawrot, T.S., Herceg, Z., Annesi‑Maesano, I., Fallin, M.D., Yeung, E., Breton, C.V., Koletzko, B., Holland, N., Melén, E., Sharp, G.C., Silver, M.J., Kadalayil, L., Alam, M., White, C.H., Ghantous, A., Walton, E., Gruzieva, O., Merid, S.K., Kumar, A., Roy, R., Solomon, O., Huen, K., Eskenazi, B., Rzehak, P., Grote, V., Langhendries, J.-P., Verduci, E., Ferre, N., Gruszfeld, D., Gao, L., Guan, W., Zeng, X., Schisterman, E.F., Dou, J., Bakulski, K.M., Feinberg, J.I., Soomro, M.H., Pesce, G., Baiz, N., Isaevska, E., Plusquin, M., Vafeiadi, M., Roumeliotaki, T., Langie, S.A.S., Standaert, A., Allard, C., Perron, P., Bouchard, L., van Meel, E.R., Felix, J.F., Jaddoe, V.W.V., Yousefi, P.D., Ramlau‑Hansen, C.H., Relton, C.L., Tobi, E.W., Starling, A.P., Yang, I.V., Llambrich, M., Santorelli, G., Lepeule, J., Salas, L.A., Bustamante, M., Ewart, S.L., Zhang, H., Karmaus, W., Röder, Stefan, Zenclussen, Ana Claudia, Jin, J., Nystad, W., Page, C.M., Magnus, M., Jima, D.D., Hoyo, C., Maguire, R.L., Kvist, T., Czamara, D., Räikkönen, K., Gong, T., Ullemar, V., Rifas‐Shiman, S.L., Oken, E., Almqvist, C., Karlsson, R., Lahti, J., Murphy, S.K., Håberg, S.E., London, S., Herberth, Gunda, Arshad, H., Sunyer, J., Grazuleviciene, R., Dabelea, D., Steegers‑Theunissen, R.P.M., Nohr, E.A., Sørensen, T.I.A., Duijts, L., Hivert, M.-F., Nelen, V., Popovic, M., Kogevinas, M., Nawrot, T.S., Herceg, Z., Annesi‑Maesano, I., Fallin, M.D., Yeung, E., Breton, C.V., Koletzko, B., Holland, N., Melén, E., Sharp, G.C., and Silver, M.J.
Abstract: BackgroundSeasonal variations in environmental exposures at birth or during gestation are associated with numerous adult traits and health outcomes later in life. Whether DNA methylation (DNAm) plays a role in the molecular mechanisms underlying the associations between birth season and lifelong phenotypes remains unclear.MethodsWe carried out epigenome-wide meta-analyses within the Pregnancy And Childhood Epigenetic Consortium to identify associations of DNAm with birth season, both at differentially methylated probes (DMPs) and regions (DMRs). Associations were examined at two time points: at birth (21 cohorts, N = 9358) and in children aged 1–11 years (12 cohorts, N = 3610). We conducted meta-analyses to assess the impact of latitude on birth season-specific associations at both time points.ResultsWe identified associations between birth season and DNAm (False Discovery Rate-adjusted p values < 0.05) at two CpGs at birth (winter-born) and four in the childhood (summer-born) analyses when compared to children born in autumn. Furthermore, we identified twenty-six differentially methylated regions (DMR) at birth (winter-born: 8, spring-born: 15, summer-born: 3) and thirty-two in childhood (winter-born: 12, spring and summer: 10 each) meta-analyses with few overlapping DMRs between the birth seasons or the two time points. The DMRs were associated with genes of known functions in tumorigenesis, psychiatric/neurological disorders, inflammation, or immunity, amongst others. Latitude-stratified meta-analyses [higher (≥ 50°N), lower (< 50°N, northern hemisphere only)] revealed differences in associations between birth season and DNAm by birth latitude. DMR analysis implicated genes with previously reported links to schizophrenia (LAX1), skin disorders (PSORS1C, LTB4R), and airway inflammation including asthma (LTB4R), present only at birth in the higher latitudes (≥ 50°N).ConclusiosIn this large epigenome-wide meta-analysis study, we provide eviden
Published: 2023

19. Analysis of DNA methylation at birth and in childhood reveals changes associated with season of birth and latitude

Author: Universitat Rovira i Virgili, Kadalayil, L; Alam, MZ; White, CH; Ghantous, A; Walton, E; Gruzieva, O; Merid, SK; Kumar, A; Roy, RP; Solomon, O; Huen, K; Eskenazi, B; Rzehak, P; Grote, V; Langhendries, JP; Verduci, E; Ferre, N; Gruszfeld, D; Gao, L; Guan, WH; Zeng, XH; Schisterman, EF; Dou, JF; Bakulski, KM; Feinberg, JI; Soomro, MH; Pesce, G; Baiz, N; Isaevska, E; Plusquin, M; Vafeiadi, M; Roumeliotaki, T; Langie, SAS; Standaert, A; Allard, C; Perron, P; Bouchard, L; van Meel, ER; Felix, JF; Jaddoe, VWV; Yousefi, PD; Ramlau-Hansen, CH; Relton, CL; Tobi, EW; Starling, AP; Yang, IV; Llambrich, M; Santorelli, G; Lepeule, J; Salas, LA; Bustamante, M; Ewart, SL; Zhang, HM; Karmaus, W; Röder, S; Zenclussen, AC; Jin, JP; Nystad, W; Page, CM; Magnus, M; Jima, DD; Hoyo, C; Maguire, RL; Kvist, T; Czamara, D; Räikkönen, K; Gong, T; Ullemar, V; Rifas-Shiman, SL; Oken, E; Almqvist, C; Karlsson, R; Lahti, J; Murphy, SK; Håberg, SE; London, S; Herberth, G; Arshad, H; Sunyer, J; Grazuleviciene, R; Dabelea, D; Steegers-Theunissen, RPM; Nohr, EA; Sorensen, TIA; Duijts, L; Hivert, MF; Nelen, V; Popovic, M; Kogevinas, M; Nawrot, TS; Herceg, Z; Annesi-Maesano, I; Fallin, MD; Yeung, EDA; Breton, CV; Koletzko, B; Holland, N; Wiemels, JL; Melén, E; Sharp, GC; Silver, MJ; Rezwan, F; Holloway, JW, Universitat Rovira i Virgili, and Kadalayil, L; Alam, MZ; White, CH; Ghantous, A; Walton, E; Gruzieva, O; Merid, SK; Kumar, A; Roy, RP; Solomon, O; Huen, K; Eskenazi, B; Rzehak, P; Grote, V; Langhendries, JP; Verduci, E; Ferre, N; Gruszfeld, D; Gao, L; Guan, WH; Zeng, XH; Schisterman, EF; Dou, JF; Bakulski, KM; Feinberg, JI; Soomro, MH; Pesce, G; Baiz, N; Isaevska, E; Plusquin, M; Vafeiadi, M; Roumeliotaki, T; Langie, SAS; Standaert, A; Allard, C; Perron, P; Bouchard, L; van Meel, ER; Felix, JF; Jaddoe, VWV; Yousefi, PD; Ramlau-Hansen, CH; Relton, CL; Tobi, EW; Starling, AP; Yang, IV; Llambrich, M; Santorelli, G; Lepeule, J; Salas, LA; Bustamante, M; Ewart, SL; Zhang, HM; Karmaus, W; Röder, S; Zenclussen, AC; Jin, JP; Nystad, W; Page, CM; Magnus, M; Jima, DD; Hoyo, C; Maguire, RL; Kvist, T; Czamara, D; Räikkönen, K; Gong, T; Ullemar, V; Rifas-Shiman, SL; Oken, E; Almqvist, C; Karlsson, R; Lahti, J; Murphy, SK; Håberg, SE; London, S; Herberth, G; Arshad, H; Sunyer, J; Grazuleviciene, R; Dabelea, D; Steegers-Theunissen, RPM; Nohr, EA; Sorensen, TIA; Duijts, L; Hivert, MF; Nelen, V; Popovic, M; Kogevinas, M; Nawrot, TS; Herceg, Z; Annesi-Maesano, I; Fallin, MD; Yeung, EDA; Breton, CV; Koletzko, B; Holland, N; Wiemels, JL; Melén, E; Sharp, GC; Silver, MJ; Rezwan, F; Holloway, JW
Abstract: Seasonal variations in environmental exposures at birth or during gestation are associated with numerous adult traits and health outcomes later in life. Whether DNA methylation (DNAm) plays a role in the molecular mechanisms underlying the associations between birth season and lifelong phenotypes remains unclear.We carried out epigenome-wide meta-analyses within the Pregnancy And Childhood Epigenetic Consortium to identify associations of DNAm with birth season, both at differentially methylated probes (DMPs) and regions (DMRs). Associations were examined at two time points: at birth (21 cohorts, N = 9358) and in children aged 1-11 years (12 cohorts, N = 3610). We conducted meta-analyses to assess the impact of latitude on birth season-specific associations at both time points.We identified associations between birth season and DNAm (False Discovery Rate-adjusted p values < 0.05) at two CpGs at birth (winter-born) and four in the childhood (summer-born) analyses when compared to children born in autumn. Furthermore, we identified twenty-six differentially methylated regions (DMR) at birth (winter-born: 8, spring-born: 15, summer-born: 3) and thirty-two in childhood (winter-born: 12, spring and summer: 10 each) meta-analyses with few overlapping DMRs between the birth seasons or the two time points. The DMRs were associated with genes of known functions in tumorigenesis, psychiatric/neurological disorders, inflammation, or immunity, amongst others. Latitude-stratified meta-analyses [higher (≥ 50°N), lower (< 50°N, northern hemisphere only)] revealed differences in associations between birth season and DNAm by birth latitude. DMR analysis implicated genes with previously reported links to schizophrenia (LAX1), skin disorders (PSORS1C, LTB4R), and airway inflammation inclu
Published: 2023

20. New insights into the genetic etiology of Alzheimer's disease and related dementias

Author: Bellenguez, C., Küçükali, F., Jansen, I. E., Kleineidam, L., Moreno-Grau, S., Amin, N., Naj, A. C., Campos-Martin, R., Grenier-Boley, B., Andrade, V., Holmans, P. A., Boland, A., Damotte, V., van der Lee, S. J., Costa, M. R., Kuulasmaa, T., Yang, Q., de Rojas, I., Bis, J. C., Yaqub, A., Prokic, I., Chapuis, J., Ahmad, S., Giedraitis, V., Aarsland, D., Garcia-Gonzalez, P., Abdelnour, C., Alarcón-Martín, E., Alcolea, D., Alegret, M., Alvarez, I., Álvarez, V., Armstrong, N. J., Tsolaki, A., Antúnez, C., Appollonio, I., Arcaro, M., Archetti, S., Pastor, A. A., Arosio, B., Athanasiu, L., Bailly, H., Banaj, N., Baquero, M., Barral, S., Beiser, A., Pastor, A. B., Below, J. E., Benchek, P., Benussi, L., Berr, C., Besse, C., Bessi, V., Binetti, G., Bizarro, A., Blesa, R., Boada, M., Boerwinkle, E., Borroni, B., Boschi, S., Bossù, P., Bråthen, G., Bressler, J., Bresner, C., Brodaty, H., Brookes, K. J., Brusco, L. I., Buiza-Rueda, D., Bûrger, K., Burholt, V., Bush, W. S., Calero, M., Cantwell, L. B., Chene, G., Chung, J., Cuccaro, M. L., Carracedo, Á., Cecchetti, R., Cervera-Carles, L., Charbonnier, C., Chen, H. -H., Chillotti, C., Ciccone, S., Claassen, J. A. H. R., Clark, C., Conti, E., Corma-Gómez, A., Costantini, E., Custodero, C., Daian, D., Dalmasso, M. C., Daniele, A., Dardiotis, E., Dartigues, J. -F., de Deyn, P. P., de Paiva Lopes, K., de Witte, L. D., Debette, S., Deckert, J., del Ser, T., Denning, N., Destefano, A., Dichgans, M., Diehl-Schmid, J., Diez-Fairen, M., Rossi, P. D., Djurovic, S., Duron, E., Düzel, E., Dufouil, C., Eiriksdottir, G., Engelborghs, S., Escott-Price, V., Espinosa, A., Ewers, M., Faber, K. M., Fabrizio, T., Nielsen, S. F., Fardo, D. W., Farotti, L., Fenoglio, C., Fernández-Fuertes, M., Ferrari, R., Ferreira, C. B., Ferri, E., Fin, B., Fischer, P., Fladby, T., Fließbach, K., Fongang, B., Fornage, M., Fortea, J., Foroud, T. M., Fostinelli, S., Fox, N. C., Franco-Macías, E., Bullido, M. J., Frank-García, A., Froelich, L., Fulton-Howard, B., Galimberti, D., García-Alberca, J. M., García-González, P., Garcia-Madrona, S., Garcia-Ribas, G., Ghidoni, R., Giegling, I., Giorgio, G., Goate, A. M., Goldhardt, O., Gomez-Fonseca, D., González-Pérez, A., Graff, C., Grande, G., Green, E., Grimmer, T., Grünblatt, E., Grunin, M., Gudnason, V., Guetta-Baranes, T., Haapasalo, A., Hadjigeorgiou, G., Haines, J. L., Hamilton-Nelson, K. L., Hampel, H., Hanon, O., Hardy, J., Hartmann, A. M., Hausner, L., Harwood, J., Heilmann-Heimbach, S., Helisalmi, S., Heneka, M. T., Hernández, I., Herrmann, M. J., Hoffmann, P., Holmes, C., Holstege, H., Vilas, R. H., Hulsman, M., Humphrey, J., Biessels, G. J., Jian, X., Johansson, C., Jun, G. R., Kastumata, Y., Kauwe, J., Kehoe, P. G., Kilander, L., Ståhlbom, A. K., Kivipelto, M., Koivisto, A., Kornhuber, J., Kosmidis, M. H., Kukull, W. A., Kuksa, P. P., Kunkle, B. W., Kuzma, A. B., Lage, C., Laukka, E. J., Launer, L., Lauria, A., Lee, C. -Y., Lehtisalo, J., Lerch, O., Lleó, A., Longstreth, W., Lopez, O., de Munain, A. L., Love, S., Löwemark, M., Luckcuck, L., Lunetta, K. L., Ma, Y., Macías, J., Macleod, C. A., Maier, W., Mangialasche, F., Spallazzi, M., Marquié, M., Marshall, R., Martin, E. R., Montes, A. M., Rodríguez, C. M., Masullo, C., Mayeux, R., Mead, S., Mecocci, P., Medina, M., Meggy, A., Mehrabian, S., Mendoza, S., Menéndez-González, M., Mir, P., Moebus, S., Mol, M., Molina-Porcel, L., Montrreal, L., Morelli, L., Moreno, F., Morgan, K., Mosley, T., Nöthen, M. M., Muchnik, C., Mukherjee, S., Nacmias, B., Ngandu, T., Nicolas, G., Nordestgaard, B. G., Olaso, R., Orellana, A., Orsini, M., Ortega, G., Padovani, A., Paolo, C., Papenberg, G., Parnetti, L., Pasquier, F., Pastor, P., Peloso, G., Pérez-Cordón, A., Pérez-Tur, J., Pericard, P., Peters, O., Pijnenburg, Y. A. L., Pineda, J. A., Piñol-Ripoll, G., Pisanu, C., Polak, T., Popp, J., Posthuma, D., Priller, J., Puerta, R., Quenez, O., Quintela, I., Thomassen, J. Q., Rábano, A., Rainero, I., Rajabli, F., Ramakers, I., Real, L. M., Reinders, M. J. T., Reitz, C., Reyes-Dumeyer, D., Ridge, P., Riedel-Heller, S., Riederer, P., Roberto, N., Rodriguez-Rodriguez, E., Rongve, A., Allende, I. R., Rosende-Roca, M., Royo, J. L., Rubino, E., Rujescu, D., Sáez, M. E., Sakka, P., Saltvedt, I., Sanabria, Á., Sánchez-Arjona, M. B., Sanchez-Garcia, F., Juan, P. S., Sánchez-Valle, R., Sando, S. B., Sarnowski, C., Satizabal, C. L., Scamosci, M., Scarmeas, N., Scarpini, E., Scheltens, P., Scherbaum, N., Scherer, M., Schmid, M., Schneider, A., Schott, J. M., Selbæk, G., Seripa, D., Serrano, M., Sha, J., Shadrin, A. A., Skrobot, O., Slifer, S., Snijders, G. J. L., Soininen, H., Solfrizzi, V., Solomon, A., Song, Y. E., Sorbi, S., Sotolongo-Grau, O., Spalletta, G., Spottke, A., Squassina, A., Stordal, E., Tartan, J. P., Tárraga, L., Tesí, N., Thalamuthu, A., Thomas, T., Tosto, G., Traykov, L., Tremolizzo, L., Tybjærg-Hansen, A., Uitterlinden, A., Ullgren, A., Ulstein, I., Valero, S., Valladares, O., Broeckhoven, C. V., Vance, J., Vardarajan, B. N., van der Lugt, A., Dongen, J. V., van Rooij, J., van Swieten, J., Vandenberghe, R., Verhey, F., Vidal, J. -S., Vogelgsang, J., Vyhnalek, M., Wagner, M., Wallon, D., Wang, L. -S., Wang, R., Weinhold, L., Wiltfang, J., Windle, G., Woods, B., Yannakoulia, M., Zare, H., Zhao, Y., Zhang, X., Zhu, C., Zulaica, M., Laczo, J., Matoska, V., Serpente, M., Assogna, F., Piras, F., Ciullo, V., Shofany, J., Ferrarese, C., Andreoni, S., Sala, G., Zoia, C. P., Zompo, M. D., Benussi, A., Bastiani, P., Takalo, M., Natunen, T., Laatikainen, T., Tuomilehto, J., Antikainen, R., Strandberg, T., Lindström, J., Peltonen, M., Abraham, R., Al-Chalabi, A., Bass, N. J., Brayne, C., Brown, K. S., Collinge, J., Craig, D., Deloukas, P., Fox, N., Gerrish, A., Gill, M., Gwilliam, R., Harold, D., Hollingworth, P., Johnston, J. A., Jones, L., Lawlor, B., Livingston, G., Lovestone, S., Lupton, M., Lynch, A., Mann, D., Mcguinness, B., Mcquillin, A., O’Donovan, M. C., Owen, M. J., Passmore, P., Powell, J. F., Proitsi, P., Rossor, M., Shaw, C. E., Smith, A. D., Gurling, H., Todd, S., Mummery, C., Ryan, N., Lacidogna, G., Adarmes-Gómez, A., Mauleón, A., Pancho, A., Gailhajenet, A., Lafuente, A., Macias-García, D., Martín, E., Pelejà, E., Carrillo, F., Merlín, I. S., Garrote-Espina, L., Vargas, L., Carrion-Claro, M., Marín, M., Labrador, M., Buendia, M., Alonso, M. D., Guitart, M., Moreno, M., Ibarria, M., Periñán, M., Aguilera, N., Gómez-Garre, P., Cañabate, P., Escuela, R., Pineda-Sánchez, R., Vigo-Ortega, R., Jesús, S., Preckler, S., Rodrigo-Herrero, S., Diego, S., Vacca, A., Roveta, F., Salvadori, N., Chipi, E., Boecker, H., Laske, C., Perneczky, R., Anastasiou, C., Janowitz, D., Malik, R., Anastasiou, A., Parveen, K., López-García, S., Antonell, A., Mihova, K. Y., Belezhanska, D., Weber, H., Kochen, S., Solis, P., Medel, N., Lisso, J., Sevillano, Z., Politis, D. G., Cores, V., Cuesta, C., Ortiz, C., Bacha, J. I., Rios, M., Saenz, A., Abalos, M. S., Kohler, E., Palacio, D. L., Etchepareborda, I., Kohler, M., Novack, G., Prestia, F. A., Galeano, P., Castaño, E. M., Germani, S., Toso, C. R., Rojo, M., Ingino, C., Mangone, C., Rubinsztein, D. C., Teipel, S., Fievet, N., Deramerourt, V., Forsell, C., Thonberg, H., Bjerke, M., Roeck, E. D., Martínez-Larrad, M. T., Olivar, N., Cano, A., Macias, J., Maroñas, O., Nuñez-Llaves, R., Olivé, C., Adarmes-Gómez, A. D., Amer-Ferrer, G., Antequera, M., Burguera, J. A., Casajeros, M. J., Martinez de Pancorbo, M., Hevilla, S., Espinosa, M. A. L., Legaz, A., Manzanares, S., Marín-Muñoz, J., Marín, T., Martínez, B., Martínez, V., Martínez-Lage Álvarez, P., Iriarte, M. M., Periñán-Tocino, M. T., Real de Asúa, D., Rodrigo, S., Sastre, I., Vicente, M. P., Vivancos, L., Epelbaum, J., Hannequin, D., Campion, D., Deramecourt, V., Tzourio, C., Brice, A., Dubois, B., Williams, A., Thomas, C., Davies, C., Nash, W., Dowzell, K., Morales, A. C., Bernardo-Harrington, M., Turton, J., Lord, J., Brown, K., Vardy, E., Fisher, E., Warren, J. D., Ryan, N. S., Guerreiro, R., Uphill, J., Bass, N., Heun, R., Kölsch, H., Schürmann, B., Lacour, A., Herold, C., Powell, J., Patel, Y., Hodges, A., Becker, T., Warden, D., Wilcock, G., Clarke, R., Ben-Shlomo, Y., Hooper, N. 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Peters, O, Pijnenburg, Y, Pineda, J, Piñol-Ripoll, G, Pisanu, C, Polak, T, Popp, J, Posthuma, D, Priller, J, Puerta, R, Quenez, O, Quintela, I, Thomassen, J, Rábano, A, Rainero, I, Rajabli, F, Ramakers, I, Real, L, Reinders, M, Reitz, C, Reyes-Dumeyer, D, Ridge, P, Riedel-Heller, S, Riederer, P, Roberto, N, Rodriguez-Rodriguez, E, Rongve, A, Allende, I, Rosende-Roca, M, Royo, J, Rubino, E, Rujescu, D, Sáez, M, Sakka, P, Saltvedt, I, Sanabria, Á, Sánchez-Arjona, M, Sanchez-Garcia, F, Juan, P, Sánchez-Valle, R, Sando, S, Sarnowski, C, Satizabal, C, Scamosci, M, Scarmeas, N, Scarpini, E, Scheltens, P, Scherbaum, N, Scherer, M, Schmid, M, Schneider, A, Schott, J, Selbæk, G, Seripa, D, Serrano, M, Sha, J, Shadrin, A, Skrobot, O, Slifer, S, Snijders, G, Soininen, H, Solfrizzi, V, Solomon, A, Song, Y, Sorbi, S, Sotolongo-Grau, O, Spalletta, G, Spottke, A, Squassina, A, Stordal, E, Tartan, J, Tárraga, L, Tesí, N, Thalamuthu, A, Thomas, T, Tosto, G, Traykov, L, Tremolizzo, L, Tybjærg-Hansen, A, 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[0000-0002-7467-250X], Soininen, Hilkka [0000-0002-2785-9937], Solfrizzi, Vincenzo [0000-0002-8524-0315], Song, Yeunjoo [0000-0002-7452-3731], Sotolongo-Grau, Oscar [0000-0002-9679-0670], Spalletta, Gianfranco [0000-0002-7432-4249], Squassina, Alessio [0000-0001-7415-7607], Stordal, Eystein [0000-0002-2443-7923], Tosto, Giuseppe [0000-0001-7075-8245], Uitterlinden, Andre [0000-0002-7276-3387], Valladares, Otto [0000-0001-8055-2187], Broeckhoven, Christine Van [0000-0003-0183-7665], Vidal, Jean-Sébastien [0000-0001-6770-0720], Vogelgsang, Jonathan [0000-0001-9326-8193], Wagner, Michael [0000-0003-2589-6440], Wallon, David [0000-0002-2634-7198], Wiltfang, Jens [0000-0003-1492-5330], Woods, Bob [0000-0002-6781-651X], Yannakoulia, Mary [0000-0003-2171-7337], Zare, Habil [0000-0001-5902-6238], Zhang, Xiaoling [0000-0001-8237-1857], Farrer, Lindsay A [0000-0001-5533-4225], Psaty, Bruce M [0000-0002-7278-2190], Ghanbari, Mohsen [0000-0002-9476-7143], Raj, Towfique [0000-0002-9355-5704], Sachdev, Perminder [0000-0002-9595-3220], Mather, Karen [0000-0003-4143-8941], Ikram, M Arfan [0000-0003-0372-8585], Tsolaki, Magda [0000-0002-2072-8010], Pericak-Vance, Margaret A [0000-0001-7283-8804], Amouyel, Philippe [0000-0001-9088-234X], Williams, Julie [0000-0002-4069-0259], Frikke-Schmidt, Ruth [0000-0003-4084-5027], Seshadri, Sudha [0000-0001-6135-2622], Andreassen, Ole A [0000-0002-4461-3568], Sleegers, Kristel [0000-0002-0283-2332], van Duijn, Cornelia M [0000-0002-2374-9204], Sims, Rebecca [0000-0002-3885-1199], van der Flier, Wiesje M [0000-0001-8766-6224], Ramirez, Alfredo [0000-0003-4991-763X], Lambert, Jean-Charles [0000-0003-0829-7817], Apollo - University of Cambridge Repository, Complex Trait Genetics, Clinical sciences, Neuroprotection & Neuromodulation, Pathologic Biochemistry and Physiology, Clinical Biology, Epidemiology, Internal Medicine, Psychiatrie & Neuropsychologie, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, MUMC+: MA Med Staf Spec Psychiatrie (9), UAM. Departamento de Biología Molecular, University of Helsinki, Department of Neurosciences, HUS Internal Medicine and Rehabilitation, Timo Strandberg / Principal Investigator, Department of Medicine, Clinicum, HUS Neurocenter, Neurologian yksikkö, Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, Institut Pasteur, Institut National de la Santé et de la Recherche Médicale (France), European Commission, LabEx DISTALZ, Pérez-Tur, Jordi, University Children’s Hospital Basel (Suiza), INSERM (Francia), Lille Métropole Communauté Urbaine, Government of France (Francia), EADB, GR@ACE, DEGESCO, EADI, GERAD, Demgene, FinnGen, ADGC, CHARGE, Holmans, Peter A. [0000-0003-0870-9412], van der Lee, Sven J. [0000-0003-1606-8643], Costa, Marcos R. [0000-0002-4928-2163], Bis, Joshua C. [0000-0002-3409-1110], Brookes, Keeley J. [0000-0003-2427-2513], Bush, William S. [0000-0002-9729-6519], de Witte, Lot D. [0000-0002-7235-9958], del Ser, Teodoro [0000-0001-9806-7083], Fox, Nick C. [0000-0002-6660-657X], Bullido, María J. [0000-0002-6477-1117], Goate, Alison M. [0000-0002-0576-2472], Herrmann, Martin J. [0000-0001-9970-2122], Jun, Gyungah R. [0000-0002-3230-8697], Kehoe, Patrick G. [0000-0002-7542-1139], Kosmidis, Mary H. [0000-0001-8790-1220], Lunetta, Kathryn L. [0000-0002-9268-810X], MacLeod, Catherine A. [0000-0002-9314-7380], Nöthen, Markus M. [0000-0002-8770-2464], Nordestgaard, Børge G. [0000-0002-1954-7220], Pineda, Juan A. [0000-0002-3751-0296], Real, Luis M. [0000-0003-4932-7429], Reinders, Marcel J. T. [0000-0002-1148-1562], Satizabal, Claudia L. [0000-0002-1115-4430], Schott, Jonathan M. [0000-0003-2059-024X], Shadrin, Alexey A. [0000-0002-7467-250X], Farrer, Lindsay A. [0000-0001-5533-4225], Psaty, Bruce M. [0000-0002-7278-2190], Ikram, M. Arfan [0000-0003-0372-8585], Pericak-Vance, Margaret A. [0000-0001-7283-8804], Andreassen, Ole A. [0000-0002-4461-3568], van Duijn, Cornelia M. [0000-0002-2374-9204], van der Flier, Wiesje M. [0000-0001-8766-6224], and Molecular Neuroscience and Ageing Research (MOLAR)
Subjects: tau Proteins/genetics, Alzheimer`s disease Donders Center for Medical Neuroscience [Radboudumc 1], Neurologi, MED/03 - GENETICA MEDICA, 45/43, Medizin, Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13], genetics [Alzheimer Disease], Genome-Wide Association Study, Humans, tau Proteins, Alzheimer Disease, Cognitive Dysfunction, VARIANTS, pathology [Alzheimer Disease], Tau Proteins, Settore BIO/13 - Biologia Applicata, Cognitive Dysfunction/psychology, 692/699/375/365/1283, IMPUTATION, article, 1184 Genetics, developmental biology, physiology, Biología y Biomedicina / Biología, AMYLOID-BETA, Settore MED/26 - NEUROLOGIA, Neurology, psychology [Cognitive Dysfunction], Medical Genetics, Human, Neuroscience(all), 631/208/205/2138, All institutes and research themes of the Radboud University Medical Center, SDG 3 - Good Health and Well-being, ddc:570, Genetics, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, METAANALYSIS, Medicinsk genetik, MED/26 - NEUROLOGIA, Alzheimer Disease/genetics, neurology, tau Protein, NECROSIS-FACTOR-ALPHA, RISK LOCI, genetics [tau Proteins], PREDICTION MODELS, Human medicine, GENERATION, RESPONSES
Abstract: 25 páginas, 6 figuras, 2 tablas, Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele., This work was funded by a grant (EADB) from the EU Joint Programme – Neurodegenerative Disease Research. INSERM UMR1167 is also funded by the INSERM, Institut Pasteur de Lille, Lille Métropole Communauté Urbaine and French government’s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to AD). Full consortium acknowledgements and funding are in the Supplementary Not
Published: 2022

21. Class inequalities in physical functioning trajectories before and after retirement

Author: Lahti, J, primary, Pietiläinen, O, additional, Rahkonen, O, additional, and Lallukka, T, additional
Published: 2022
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22. Clustering of unhealthy behaviours and subsequent sickness absence among Finnish municipal employees

Author: Salmela, J, primary, Lahti, J, additional, Kanerva, N, additional, Rahkonen, O, additional, Kouvonen, A, additional, and Lallukka, T, additional
Published: 2022
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23. Weight gain and subsequent diagnosis-specific sickness absence: A register-linked follow-up study: Anna Svärd

Author: Lahti, J, Mänty, M, Roos, E, Rahkonen, O, Lahelma, E, Lallukka, T, and Svärd, A
Published: 2017
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24. An epigenome-wide association study meta-analysis of educational attainment

Author: Linnér, R Karlsson, Marioni, R E, Rietveld, C A, Simpkin, A J, Davies, N M, Watanabe, K, Armstrong, N J, Auro, K, Baumbach, C, Bonder, M J, Buchwald, J, Fiorito, G, Ismail, K, Iurato, S, Joensuu, A, Karell, P, Kasela, S, Lahti, J, McRae, A F, Mandaviya, P R, Seppälä, I, Wang, Y, Baglietto, L, Binder, E B, Harris, S E, Hodge, A M, Horvath, S, Hurme, M, Johannesson, M, Latvala, A, Mather, K A, Medland, S E, Metspalu, A, Milani, L, Milne, R L, Pattie, A, Pedersen, N L, Peters, A, Polidoro, S, Räikkönen, K, Severi, G, Starr, J M, Stolk, L, Waldenberger, M, Consortium, B IOS, Eriksson, J G, Esko, T, Franke, L, Gieger, C, Giles, G G, Hägg, S, Jousilahti, P, Kaprio, J, Kähönen, M, Lehtimäki, T, Martin, N G, van Meurs, J BC, Ollikainen, M, Perola, M, Posthuma, D, Raitakari, O T, Sachdev, P S, Taskesen, E, Uitterlinden, A G, Vineis, P, Wijmenga, C, Wright, M J, Relton, C, Smith, G Davey, Deary, I J, Koellinger, P D, and Benjamin, D J
Published: 2017
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25. Meta-analysis of epigenome-wide association studies in newborns and children show widespread sex differences in blood DNA methylation.

Author: Solomon, O, Huen, K, Yousefi, P, Küpers, LK, González, JR, Suderman, M, Reese, SE, Page, CM, Gruzieva, O, Rzehak, P, Gao, L, Bakulski, KM, Novoloaca, A, Allard, C, Pappa, I, Llambrich, M, Vives, M, Jima, DD, Kvist, T, Baccarelli, A, White, C, Rezwan, FI, Sharp, GC, Tindula, G, Bergström, A, Grote, V, Dou, JF, Isaevska, E, Magnus, MC, Corpeleijn, E, Perron, P, Jaddoe, VWV, Nohr, EA, Maitre, L, Foraster, M, Hoyo, C, Håberg, SE, Lahti, J, DeMeo, DL, Zhang, H, Karmaus, W, Kull, I, Koletzko, B, Feinberg, JI, Gagliardi, L, Bouchard, L, Ramlau-Hansen, CH, Tiemeier, H, Santorelli, G, Maguire, RL, Czamara, D, Litonjua, AA, Langhendries, J-P, Plusquin, M, Lepeule, J, Binder, EB, Verduci, E, Dwyer, T, Carracedo, Á, Ferre, N, Eskenazi, B, Kogevinas, M, Nawrot, TS, Munthe-Kaas, MC, Herceg, Z, Relton, C, Melén, E, Gruszfeld, D, Breton, C, Fallin, MD, Ghantous, A, Nystad, W, Heude, B, Snieder, H, Hivert, M-F, Felix, JF, Sørensen, TIA, Bustamante, M, Murphy, SK, Raikkönen, K, Oken, E, Holloway, JW, Arshad, SH, London, SJ, Holland, N, Solomon, O, Huen, K, Yousefi, P, Küpers, LK, González, JR, Suderman, M, Reese, SE, Page, CM, Gruzieva, O, Rzehak, P, Gao, L, Bakulski, KM, Novoloaca, A, Allard, C, Pappa, I, Llambrich, M, Vives, M, Jima, DD, Kvist, T, Baccarelli, A, White, C, Rezwan, FI, Sharp, GC, Tindula, G, Bergström, A, Grote, V, Dou, JF, Isaevska, E, Magnus, MC, Corpeleijn, E, Perron, P, Jaddoe, VWV, Nohr, EA, Maitre, L, Foraster, M, Hoyo, C, Håberg, SE, Lahti, J, DeMeo, DL, Zhang, H, Karmaus, W, Kull, I, Koletzko, B, Feinberg, JI, Gagliardi, L, Bouchard, L, Ramlau-Hansen, CH, Tiemeier, H, Santorelli, G, Maguire, RL, Czamara, D, Litonjua, AA, Langhendries, J-P, Plusquin, M, Lepeule, J, Binder, EB, Verduci, E, Dwyer, T, Carracedo, Á, Ferre, N, Eskenazi, B, Kogevinas, M, Nawrot, TS, Munthe-Kaas, MC, Herceg, Z, Relton, C, Melén, E, Gruszfeld, D, Breton, C, Fallin, MD, Ghantous, A, Nystad, W, Heude, B, Snieder, H, Hivert, M-F, Felix, JF, Sørensen, TIA, Bustamante, M, Murphy, SK, Raikkönen, K, Oken, E, Holloway, JW, Arshad, SH, London, SJ, and Holland, N
Abstract: BACKGROUND: Among children, sex-specific differences in disease prevalence, age of onset, and susceptibility have been observed in health conditions including asthma, immune response, metabolic health, some pediatric and adult cancers, and psychiatric disorders. Epigenetic modifications such as DNA methylation may play a role in the sexual differences observed in diseases and other physiological traits. METHODS: We performed a meta-analysis of the association of sex and cord blood DNA methylation at over 450,000 CpG sites in 8438 newborns from 17 cohorts participating in the Pregnancy And Childhood Epigenetics (PACE) Consortium. We also examined associations of child sex with DNA methylation in older children ages 5.5-10 years from 8 cohorts (n = 4268). RESULTS: In newborn blood, sex was associated at Bonferroni level significance with differences in DNA methylation at 46,979 autosomal CpG sites (p < 1.3 × 10-7) after adjusting for white blood cell proportions and batch. Most of those sites had lower methylation levels in males than in females. Of the differentially methylated CpG sites identified in newborn blood, 68% (31,727) met look-up level significance (p < 1.1 × 10-6) in older children and had methylation differences in the same direction. CONCLUSIONS: This is a large-scale meta-analysis examining sex differences in DNA methylation in newborns and older children. Expanding upon previous studies, we replicated previous findings and identified additional autosomal sites with sex-specific differences in DNA methylation. Differentially methylated sites were enriched in genes involved in cancer, psychiatric disorders, and cardiovascular phenotypes.
Published: 2022

26. Uncovering the genetic architecture of broad antisocial behavior through a genome-wide association study meta-analysis

Author: Tielbeek, J.J., Uffelmann, E., Williams, B.S., Colodro-Conde, L., Gagnon, É., Mallard, T.T., Levitt, B.E., Jansen, P.R., Johansson, A, Sallis, H.M., Pistis, G., Saunders, G.R.B., Allegrini, A.G., Rimfeld, K., Konte, B., Klein, M., Hartmann, A.M., Salvatore, J.E., Nolte, I.M., Demontis, D., Malmberg, A.L.K., Burt, S.A., Savage, J.E., Sugden, K., Poulton, R., Harris, K.M., Vrieze, S., McGue, M., Iacono, W.G., Roth Mota, N., Mill, J., Viana, J.F., Mitchell, B.L., Morosoli, J.J., Andlauer, T.F.M., Ouellet-Morin, I., Tremblay, R.E., Côté, S.M., Gouin, J.-P., Brendgen, M.R., Dionne, G., Vitaro, F., Lupton, M.K., Martin, N.G., Porjesz, B., Hesselbrock, V., Foroud, T., Agrawal, A., Edenberg, H.J., Liu, Y, Plawecki, M.H., Kuperman, S., Kramer, J.R., Meyers, J.M., Kamarajan, C., Pandey, A., Bierut, L., Rice, J., Bucholz, K.K., Schuckit, M.A., Tischfield, J., Hart, R., Almasy, L., Goate, A., Slesinger, P., Scott, D., Castelao, E., Räikkönen, K., Eriksson, J.G., Lahti, J., Hartman, C.A, Oldehinkel, A.J., Snieder, H., Liu, H., Preisig, M., Whipp, A., Vuoksimaa, E., Lu, Y., Jern, P., Rujescu, D., Giegling, I., Palviainen, T., Kaprio, J., Harden, K.P., Munafò, M.R., Morneau-Vaillancourt, G., Plomin, R., Viding, E., Boutwell, B.B., Aliev, F., Dick, D.M., Popma, A., Faraone, S.V, Børglum, A.D., Medland, S.E., Franke, B., Boivin, M., Pingault, J.-B., Glennon, J.C., Barnes, J.C., Fisher, S.E., Tielbeek, J.J., Uffelmann, E., Williams, B.S., Colodro-Conde, L., Gagnon, É., Mallard, T.T., Levitt, B.E., Jansen, P.R., Johansson, A, Sallis, H.M., Pistis, G., Saunders, G.R.B., Allegrini, A.G., Rimfeld, K., Konte, B., Klein, M., Hartmann, A.M., Salvatore, J.E., Nolte, I.M., Demontis, D., Malmberg, A.L.K., Burt, S.A., Savage, J.E., Sugden, K., Poulton, R., Harris, K.M., Vrieze, S., McGue, M., Iacono, W.G., Roth Mota, N., Mill, J., Viana, J.F., Mitchell, B.L., Morosoli, J.J., Andlauer, T.F.M., Ouellet-Morin, I., Tremblay, R.E., Côté, S.M., Gouin, J.-P., Brendgen, M.R., Dionne, G., Vitaro, F., Lupton, M.K., Martin, N.G., Porjesz, B., Hesselbrock, V., Foroud, T., Agrawal, A., Edenberg, H.J., Liu, Y, Plawecki, M.H., Kuperman, S., Kramer, J.R., Meyers, J.M., Kamarajan, C., Pandey, A., Bierut, L., Rice, J., Bucholz, K.K., Schuckit, M.A., Tischfield, J., Hart, R., Almasy, L., Goate, A., Slesinger, P., Scott, D., Castelao, E., Räikkönen, K., Eriksson, J.G., Lahti, J., Hartman, C.A, Oldehinkel, A.J., Snieder, H., Liu, H., Preisig, M., Whipp, A., Vuoksimaa, E., Lu, Y., Jern, P., Rujescu, D., Giegling, I., Palviainen, T., Kaprio, J., Harden, K.P., Munafò, M.R., Morneau-Vaillancourt, G., Plomin, R., Viding, E., Boutwell, B.B., Aliev, F., Dick, D.M., Popma, A., Faraone, S.V, Børglum, A.D., Medland, S.E., Franke, B., Boivin, M., Pingault, J.-B., Glennon, J.C., Barnes, J.C., and Fisher, S.E.
Abstract: Item does not contain fulltext
Published: 2022

27. Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning

Author: Lahti, J., Tuominen, S., Yang, Q., Pergola, G., Ahmad, S., Amin, N., Armstrong, N.J., Beiser, A., Bey, K., Bis, J.C., Boerwinkle, E., Bressler, J., Campbell, A., Campbell, H., Chen, Q., Corley, J., Cox, S.R., Davies, G., De Jager, P.L., Derks, E.M., Faul, J.D., Fitzpatrick, A.L., Fohner, A.E., Ford, I., Fornage, M., Gerring, Z., Grabe, H.J., Grodstein, F., Gudnason, V., Simonsick, E., Holliday, E.G., Joshi, P.K., Kajantie, E., Kaprio, J., Karell, P., Kleineidam, L., Knol, M.J., Kochan, N.A., Kwok, J.B., Leber, M., Lam, M., Lee, T., Li, S., Loukola, A., Luck, T., Marioni, R.E., Mather, K.A., Medland, S., Mirza, S.S., Nalls, M.A., Nho, K., O’Donnell, A., Oldmeadow, C., Painter, J., Pattie, A., Reppermund, S., Risacher, S.L., Rose, R.J., Sadashivaiah, V., Scholz, M., Satizabal, C.L., Schofield, P.W., Schraut, K.E., Scott, R.J., Simino, J., Smith, A.V., Smith, J.A., Stott, D.J., Surakka, I., Teumer, A., Thalamuthu, A., Trompet, S., Turner, S.T., van der Lee, S.J., Villringer, A., Völker, U., Wilson, R.S., Wittfeld, K., Vuoksimaa, E., Xia, R., Yaffe, K., Yu, L., Zare, H., Zhao, W., Ames, D., Attia, J., Bennett, D.A., Brodaty, H., Chasman, D.I., Goldman, A.L., Hayward, C., Ikram, M.A., Jukema, J.W., Kardia, S.L.R., Lencz, T., Loeffler, M., Mattay, V.S., Palotie, A., Psaty, B.M., Ramirez, A., Ridker, P.M., Riedel-Heller, S.G., Sachdev, P.S., Saykin, A.J., Scherer, M., Schofield, P.R., Sidney, S., Starr, J.M., Trollor, J., Ulrich, W., Wagner, M., Weir, D.R., Wilson, J.F., Wright, M.J., Weinberger, D.R., Debette, S., Eriksson, J.G., Mosley, T.H., Launer, L.J., van Duijn, C.M., Deary, I.J., Seshadri, S., Räikkönen, K., Lahti, J., Tuominen, S., Yang, Q., Pergola, G., Ahmad, S., Amin, N., Armstrong, N.J., Beiser, A., Bey, K., Bis, J.C., Boerwinkle, E., Bressler, J., Campbell, A., Campbell, H., Chen, Q., Corley, J., Cox, S.R., Davies, G., De Jager, P.L., Derks, E.M., Faul, J.D., Fitzpatrick, A.L., Fohner, A.E., Ford, I., Fornage, M., Gerring, Z., Grabe, H.J., Grodstein, F., Gudnason, V., Simonsick, E., Holliday, E.G., Joshi, P.K., Kajantie, E., Kaprio, J., Karell, P., Kleineidam, L., Knol, M.J., Kochan, N.A., Kwok, J.B., Leber, M., Lam, M., Lee, T., Li, S., Loukola, A., Luck, T., Marioni, R.E., Mather, K.A., Medland, S., Mirza, S.S., Nalls, M.A., Nho, K., O’Donnell, A., Oldmeadow, C., Painter, J., Pattie, A., Reppermund, S., Risacher, S.L., Rose, R.J., Sadashivaiah, V., Scholz, M., Satizabal, C.L., Schofield, P.W., Schraut, K.E., Scott, R.J., Simino, J., Smith, A.V., Smith, J.A., Stott, D.J., Surakka, I., Teumer, A., Thalamuthu, A., Trompet, S., Turner, S.T., van der Lee, S.J., Villringer, A., Völker, U., Wilson, R.S., Wittfeld, K., Vuoksimaa, E., Xia, R., Yaffe, K., Yu, L., Zare, H., Zhao, W., Ames, D., Attia, J., Bennett, D.A., Brodaty, H., Chasman, D.I., Goldman, A.L., Hayward, C., Ikram, M.A., Jukema, J.W., Kardia, S.L.R., Lencz, T., Loeffler, M., Mattay, V.S., Palotie, A., Psaty, B.M., Ramirez, A., Ridker, P.M., Riedel-Heller, S.G., Sachdev, P.S., Saykin, A.J., Scherer, M., Schofield, P.R., Sidney, S., Starr, J.M., Trollor, J., Ulrich, W., Wagner, M., Weir, D.R., Wilson, J.F., Wright, M.J., Weinberger, D.R., Debette, S., Eriksson, J.G., Mosley, T.H., Launer, L.J., van Duijn, C.M., Deary, I.J., Seshadri, S., and Räikkönen, K.
Abstract: Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.
Published: 2022

28. Genome-wide copy number variant and high-throughput transcriptomics analyses of placental tissues underscore persisting child susceptibility in at-risk pregnancies cleared in standard genetic testing

Author: Czamara, D. (Darina), Cruceanu, C. (Cristiana), Lahti-Pulkkinen, M. (Marius), Dieckmann, L. (Linda), Ködel, M. (Maik), Sauer, S. (Susann), Rex-Haffner, M. (Monika), Sammallahti, S. (Sara), Kajantie, E. (Eero), Laivuori, H. (Hannele), Lahti, J. (Jari), Räikkönen, K. (Katri), Binder, E. B. (Elisabeth B.), Czamara, D. (Darina), Cruceanu, C. (Cristiana), Lahti-Pulkkinen, M. (Marius), Dieckmann, L. (Linda), Ködel, M. (Maik), Sauer, S. (Susann), Rex-Haffner, M. (Monika), Sammallahti, S. (Sara), Kajantie, E. (Eero), Laivuori, H. (Hannele), Lahti, J. (Jari), Räikkönen, K. (Katri), and Binder, E. B. (Elisabeth B.)
Abstract: Several studies have shown that children from pregnancies with estimated first-trimester risk based on fetal nuchal translucency thickness and abnormal maternal serum pregnancy protein and hormone levels maintain a higher likelihood of adverse outcomes, even if initial testing for known genetic conditions is negative. We used the Finnish InTraUterine cohort (ITU), which is a comprehensively characterized perinatal cohort consisting of 943 mothers and their babies followed throughout pregnancy and 18 months postnatally, including mothers shortlisted for prenatal genetic testing but cleared for major aneuploidies (cases: n = 544, 57.7%) and control pregnancies (n = 399, 42.3%). Using genome-wide genotyping and RNA sequencing of first-trimester and term placental tissue, combined with medical information from registry data and maternal self-report data, we investigated potential negative medical outcomes and genetic susceptibility to disease and their correlates in placenta gene expression. Case mothers did not present with higher levels of depression, perceived stress, or anxiety during pregnancy. Case children were significantly diagnosed more often with congenital malformations of the circulatory system (4.12 (95% CI [1.22–13.93]) higher hazard) and presented with significantly more copy number duplications as compared to controls (burden analysis, based on all copy number variants (CNVs) with at most 10% frequency, 823 called duplications in 297 cases versus 626 called duplications in 277 controls, p = 0.01). Fifteen genes showed differential gene expression (FDR < 0.1) in association with congenital malformations in first-trimester but not term placenta. These were significantly enriched for genes associated with placental dysfunction. In spite of normal routine follow-up prenatal testing results in early pregnancy, case children presented with an increased likelihood of negative outcomes, which should prompt vigilance in follow-up during pregnancy and
Published: 2022

29. Maternal early-pregnancy body mass index-associated metabolomic component and mental and behavioral disorders in children

Author: Girchenko, P. (Polina), Lahti-Pulkkinen, M. (Marius), Lipsanen, J. (Jari), Heinonen, K. (Kati), Lahti, J. (Jari), Rantalainen, V. (Ville), Hämäläinen, E. (Esa), Laivuori, H. (Hannele), Villa, P. M. (Pia M.), Kajantie, E. (Eero), Räikkönen, K. (Katri), Girchenko, P. (Polina), Lahti-Pulkkinen, M. (Marius), Lipsanen, J. (Jari), Heinonen, K. (Kati), Lahti, J. (Jari), Rantalainen, V. (Ville), Hämäläinen, E. (Esa), Laivuori, H. (Hannele), Villa, P. M. (Pia M.), Kajantie, E. (Eero), and Räikkönen, K. (Katri)
Abstract: Maternal pre-pregnancy obesity and/or higher body mass index (BMI) have been associated with neurodevelopmental and mental health adversities in children. While maternal metabolomic perturbations during pregnancy may underpin these associations, the existing evidence is limited to studying individual metabolites, not capturing metabolic variation specific to maternal BMI, and not accounting for the correlated nature of the metabolomic measures. By using multivariate supervised analytical methods, we first identified maternal early-pregnancy BMI-associated metabolomic component during pregnancy. We then examined whether this component was associated with mental and behavioral disorders in children, improved the prediction of the child outcomes over maternal BMI, and what proportion of the effect of maternal BMI on the child outcomes this component mediated. Early-pregnancy BMI of 425 mothers participating in the PREDO study was extracted from the national Medical Birth Register. During pregnancy, mothers donated up to three blood samples, from which a targeted panel of 68 metabolites were measured. Mental and behavioral disorders in children followed-up from birth until 8.4–12.8 years came from the Care Register for Health Care. Of the 68 metabolites averaged across the three sampling points, 43 associated significantly with maternal early-pregnancy BMI yielding a maternal early-pregnancy BMI-associated metabolomic component (total variance explained, 55.4%; predictive ability, 52.0%). This metabolomic component was significantly associated with higher hazard of any mental and behavioral disorder [HR 1.45, 95%CI(1.15, 1.84)] and relative risk of having a higher number of co-morbid disorders [RR 1.43, 95%CI(1.12, 1.69)] in children. It improved the goodness-of-model-fit over maternal BMI by 37.7–65.6%, and hence the predictive significance of the model, and mediated 60.8–75.8% of the effect of maternal BMI on the child outcomes. Maternal BMI-related metabolom
Published: 2022

30. Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning

Author: Lahti, J, Tuominen, S, Yang, Q, Pergola, G, Ahmad, S, Amin, N, Armstrong, NJ, Beiser, A, Bey, K, Bis, JC, Boerwinkle, E, Bressler, J, Campbell, A, Campbell, H, Chen, Q, Corley, J, Cox, SR, Davies, G, De Jager, PL, Derks, EM, Faul, JD, Fitzpatrick, AL, Fohner, AE, Ford, I, Fornage, M, Gerring, Z, Grabe, HJ, Grodstein, F, Gudnason, V, Simonsick, E, Holliday, EG, Joshi, PK, Kajantie, E, Kaprio, J, Karell, P, Kleineidam, L, Knol, MJ, Kochan, NA, Kwok, JB, Leber, M, Lam, M, Lee, T, Li, S, Loukola, A, Luck, T, Marioni, RE, Mather, KA, Medland, S, Mirza, SS, Nalls, MA, Nho, K, O'Donnell, A, Oldmeadow, C, Painter, J, Pattie, A, Reppermund, S, Risacher, SL, Rose, RJ, Sadashivaiah, V, Scholz, M, Satizabal, CL, Schofield, PW, Schraut, KE, Scott, RJ, Simino, J, Smith, AV, Smith, JA, Stott, DJ, Surakka, I, Teumer, A, Thalamuthu, A, Trompet, S, Turner, ST, van der Lee, SJ, Villringer, A, Voelker, U, Wilson, RS, Wittfeld, K, Vuoksimaa, E, Xia, R, Yaffe, K, Yu, L, Zare, H, Zhao, W, Ames, D, Attia, J, Bennett, DA, Brodaty, H, Chasman, DI, Goldman, AL, Hayward, C, Ikram, MA, Jukema, JW, Kardia, SLR, Lencz, T, Loeffler, M, Mattay, VS, Palotie, A, Psaty, BM, Ramirez, A, Ridker, PM, Riedel-Heller, SG, Sachdev, PS, Saykin, AJ, Scherer, M, Schofield, PR, Sidney, S, Starr, JM, Trollor, J, Ulrich, W, Wagner, M, Weir, DR, Wilson, JF, Wright, MJ, Weinberger, DR, Debette, S, Eriksson, JG, Mosley, TH, Launer, LJ, van Duijn, CM, Deary, IJ, Seshadri, S, Raikkonen, K, Lahti, J, Tuominen, S, Yang, Q, Pergola, G, Ahmad, S, Amin, N, Armstrong, NJ, Beiser, A, Bey, K, Bis, JC, Boerwinkle, E, Bressler, J, Campbell, A, Campbell, H, Chen, Q, Corley, J, Cox, SR, Davies, G, De Jager, PL, Derks, EM, Faul, JD, Fitzpatrick, AL, Fohner, AE, Ford, I, Fornage, M, Gerring, Z, Grabe, HJ, Grodstein, F, Gudnason, V, Simonsick, E, Holliday, EG, Joshi, PK, Kajantie, E, Kaprio, J, Karell, P, Kleineidam, L, Knol, MJ, Kochan, NA, Kwok, JB, Leber, M, Lam, M, Lee, T, Li, S, Loukola, A, Luck, T, Marioni, RE, Mather, KA, Medland, S, Mirza, SS, Nalls, MA, Nho, K, O'Donnell, A, Oldmeadow, C, Painter, J, Pattie, A, Reppermund, S, Risacher, SL, Rose, RJ, Sadashivaiah, V, Scholz, M, Satizabal, CL, Schofield, PW, Schraut, KE, Scott, RJ, Simino, J, Smith, AV, Smith, JA, Stott, DJ, Surakka, I, Teumer, A, Thalamuthu, A, Trompet, S, Turner, ST, van der Lee, SJ, Villringer, A, Voelker, U, Wilson, RS, Wittfeld, K, Vuoksimaa, E, Xia, R, Yaffe, K, Yu, L, Zare, H, Zhao, W, Ames, D, Attia, J, Bennett, DA, Brodaty, H, Chasman, DI, Goldman, AL, Hayward, C, Ikram, MA, Jukema, JW, Kardia, SLR, Lencz, T, Loeffler, M, Mattay, VS, Palotie, A, Psaty, BM, Ramirez, A, Ridker, PM, Riedel-Heller, SG, Sachdev, PS, Saykin, AJ, Scherer, M, Schofield, PR, Sidney, S, Starr, JM, Trollor, J, Ulrich, W, Wagner, M, Weir, DR, Wilson, JF, Wright, MJ, Weinberger, DR, Debette, S, Eriksson, JG, Mosley, TH, Launer, LJ, van Duijn, CM, Deary, IJ, Seshadri, S, and Raikkonen, K
Abstract: Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.
Published: 2022

31. Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes

Author: Pervjakova, N. (Natalia), Moen, G.-H. (Gunn-Helen), Borges, M.-C. (Maria-Carolina), Ferreira, T. (Teresa), Cook, J. P. (James P.), Allard, C. (Catherine), Beaumont, R. N. (Robin N.), Canouil, M. (Mickael), Hatem, G. (Gad), Heiskala, A. (Anni), Joensuu, A. (Anni), Karhunen, V. (Ville), Kwak, S. H. (Soo Heon), Lin, F. T. (Frederick T. J.), Liu, J. (Jun), Rifas-Shiman, S. (Sheryl), Tam, C. H. (Claudia H.), Tam, W. H. (Wing Hung), Thorleifsson, G. (Gudmar), Andrew, T. (Toby), Auvinen, J. (Juha), Bhowmik, B. (Bishwajit), Bonnefond, A. (Amelie), Delahaye, F. (Fabien), Demirkan, A. (Ayse), Froguel, P. (Philippe), Haller-Kikkatalo, K. (Kadri), Hardardottir, H. (Hildur), Hummel, S. (Sandra), Hussain, A. (Akhtar), Kajantie, E. (Eero), Keikkala, E. (Elina), Khamis, A. (Amna), Lahti, J. (Jari), Lekva, T. (Tove), Mustaniemi, S. (Sanna), Sommer, C. (Christine), Tagoma, A. (Aili), Tzala, E. (Evangelia), Uibo, R. (Raivo), Vääräsmäki, M. (Marja), Villa, P. M. (Pia M.), Birkeland, K. I. (Kare, I), Bouchard, L. (Luigi), Duijn, C. M. (Cornelia M.), Finer, S. (Sarah), Groop, L. (Leif), Hamalainen, E. (Esa), Hayes, G. M. (Geoffrey M.), Hitman, G. A. (Graham A.), Jang, H. C. (Hak C.), Järvelin, M.-R. (Marjo-Riitta), Jenum, A. K. (Anne Karen), Laivuori, H. (Hannele), Ma, R. C. (Ronald C.), Melander, O. (Olle), Oken, E. (Emily), Park, K. S. (Kyong Soo), Perron, P. (Patrice), Prasad, R. B. (Rashmi B.), Qvigstad, E. (Elisabeth), Sebert, S. (Sylvain), Stefansson, K. (Kari), Steinthorsdottir, V. (Valgerdur), Tuomi, T. (Tiinamaija), Hivert, M.-F. (Marie-France), Franks, P. W. (Paul W.), McCarthy, M. I. (Mark, I), Lindgren, C. M. (Cecilia M.), Freathy, R. M. (Rachel M.), Lawlor, D. A. (Deborah A.), Morris, A. P. (Andrew P.), Magi, R. (Reedik), Pervjakova, N. (Natalia), Moen, G.-H. (Gunn-Helen), Borges, M.-C. (Maria-Carolina), Ferreira, T. (Teresa), Cook, J. P. (James P.), Allard, C. (Catherine), Beaumont, R. N. (Robin N.), Canouil, M. (Mickael), Hatem, G. (Gad), Heiskala, A. (Anni), Joensuu, A. (Anni), Karhunen, V. (Ville), Kwak, S. H. (Soo Heon), Lin, F. T. (Frederick T. J.), Liu, J. (Jun), Rifas-Shiman, S. (Sheryl), Tam, C. H. (Claudia H.), Tam, W. H. (Wing Hung), Thorleifsson, G. (Gudmar), Andrew, T. (Toby), Auvinen, J. (Juha), Bhowmik, B. (Bishwajit), Bonnefond, A. (Amelie), Delahaye, F. (Fabien), Demirkan, A. (Ayse), Froguel, P. (Philippe), Haller-Kikkatalo, K. (Kadri), Hardardottir, H. (Hildur), Hummel, S. (Sandra), Hussain, A. (Akhtar), Kajantie, E. (Eero), Keikkala, E. (Elina), Khamis, A. (Amna), Lahti, J. (Jari), Lekva, T. (Tove), Mustaniemi, S. (Sanna), Sommer, C. (Christine), Tagoma, A. (Aili), Tzala, E. (Evangelia), Uibo, R. (Raivo), Vääräsmäki, M. (Marja), Villa, P. M. (Pia M.), Birkeland, K. I. (Kare, I), Bouchard, L. (Luigi), Duijn, C. M. (Cornelia M.), Finer, S. (Sarah), Groop, L. (Leif), Hamalainen, E. (Esa), Hayes, G. M. (Geoffrey M.), Hitman, G. A. (Graham A.), Jang, H. C. (Hak C.), Järvelin, M.-R. (Marjo-Riitta), Jenum, A. K. (Anne Karen), Laivuori, H. (Hannele), Ma, R. C. (Ronald C.), Melander, O. (Olle), Oken, E. (Emily), Park, K. S. (Kyong Soo), Perron, P. (Patrice), Prasad, R. B. (Rashmi B.), Qvigstad, E. (Elisabeth), Sebert, S. (Sylvain), Stefansson, K. (Kari), Steinthorsdottir, V. (Valgerdur), Tuomi, T. (Tiinamaija), Hivert, M.-F. (Marie-France), Franks, P. W. (Paul W.), McCarthy, M. I. (Mark, I), Lindgren, C. M. (Cecilia M.), Freathy, R. M. (Rachel M.), Lawlor, D. A. (Deborah A.), Morris, A. P. (Andrew P.), and Magi, R. (Reedik)
Abstract: Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy Consortium assembled genome-wide association studies of diverse ancestry in a total of 5485 women with GDM and 347 856 without GDM. Through multi-ancestry meta-analysis, we identified five loci with genome-wide significant association (P < 5 x 10-8) with GDM, mapping to/near MTNR1B (P = 4.3 x 10-54), TCF7L2 (P = 4.0 x 10-16), CDKAL1 (P = 1.6 x 10-14), CDKN2A-CDKN2B (P = 4.1 x 10-9) and HKDC1 (P = 2.9 x 10-8). Multiple lines of evidence pointed to the shared pathophysiology of GDM and T2D: (i) four of the five GDM loci (not HKDC1) have been previously reported at genome-wide significance for T2D; (ii) significant enrichment for associations with GDM at previously reported T2D loci; (iii) strong genetic correlation between GDM and T2D and (iv) enrichment of GDM associations mapping to genomic annotations in diabetes-relevant tissues and transcription factor binding sites. Mendelian randomization analyses demonstrated significant causal association (5% false discovery rate) of higher body mass index on increased GDM risk. Our results provide support for the hypothesis that GDM and T2D are part of the same underlying pathology but that, as exemplified by the HKDC1 locus, there are genetic determinants of GDM that are specific to glucose regulation in pregnancy.
Published: 2022

32. Reliability of a novel approach for reference-based cell type estimation in human placental DNA methylation studies

Author: Dieckmann, L. (Linda), Cruceanu, C. (Cristiana), Lahti-Pulkkinen, M. (Marius), Lahti, J. (Jari), Kvist, T. (Tuomas), Laivuori, H. (Hannele), Sammallahti, S. (Sara), Villa, P. M. (Pia M.), Suomalainen-König, S. (Sanna), Rancourt, R. C. (Rebecca C.), Plagemann, A. (Andreas), Henrich, W. (Wolfgang), Eriksson, J. G. (Johan G.), Kajantie, E. (Eero), Entringer, S. (Sonja), Braun, T. (Thorsten), Räikkönen, K. (Katri), Binder, E. B. (Elisabeth B.), Czamara, D. (Darina), Dieckmann, L. (Linda), Cruceanu, C. (Cristiana), Lahti-Pulkkinen, M. (Marius), Lahti, J. (Jari), Kvist, T. (Tuomas), Laivuori, H. (Hannele), Sammallahti, S. (Sara), Villa, P. M. (Pia M.), Suomalainen-König, S. (Sanna), Rancourt, R. C. (Rebecca C.), Plagemann, A. (Andreas), Henrich, W. (Wolfgang), Eriksson, J. G. (Johan G.), Kajantie, E. (Eero), Entringer, S. (Sonja), Braun, T. (Thorsten), Räikkönen, K. (Katri), Binder, E. B. (Elisabeth B.), and Czamara, D. (Darina)
Abstract: The placenta is a central organ during early development, influencing trajectories of health and disease. DNA methylation (DNAm) studies of human placenta improve our understanding of how its function relates to disease risk. However, DNAm studies can be biased by cell type heterogeneity, so it is essential to control for this in order to reduce confounding and increase precision. Computational cell type deconvolution approaches have proven to be very useful for this purpose. For human placenta, however, an assessment of the performance of these estimation methods is still lacking. Here, we examine the performance of a newly available reference-based cell type estimation approach and compare it to an often-used reference-free cell type estimation approach, namely RefFreeEWAS, in placental genome-wide DNAm samples taken at birth and from chorionic villus biopsies early in pregnancy using three independent studies comprising over 1000 samples. We found both reference-free and reference-based estimated cell type proportions to have predictive value for DNAm, however, reference-based cell type estimation outperformed reference-free estimation for the majority of data sets. Reference-based cell type estimations mirror previous histological knowledge on changes in cell type proportions through gestation. Further, CpGs whose variation in DNAm was largely explained by reference-based estimated cell type proportions were in the proximity of genes that are highly tissue-specific for placenta. This was not the case for reference-free estimated cell type proportions. We provide a list of these CpGs as a resource to help researchers to interpret results of existing studies and improve future DNAm studies of human placenta.
Published: 2022

33. Maternal haemoglobin levels in pregnancy and child DNA methylation:a study in the pregnancy and childhood epigenetics consortium

Author: Ronkainen, J. (Justiina), Heiskala, A. (Anni), Vehmeijer, F. O. (Florianne O. L.), Lowry, E. (Estelle), Caramaschi, D. (Doretta), Estrada Gutierrez, G. (Guadalupe), Heiss, J. A. (Jonathan A.), Hummel, N. (Nadine), Keikkala, E. (Elina), Kvist, T. (Tuomas), Kupsco, A. (Allison), Melton, P. E. (Phillip E.), Pesce, G. (Giancarlo), Soomro, M. H. (Munawar H.), Vives-Usano, M. (Marta), Baiz, N. (Nour), Binder, E. (Elisabeth), Czamara, D. (Darina), Guxens, M. (Mònica), Mustaniemi, S. (Sanna), London, S. J. (Stephanie J.), Rauschert, S. (Sebastian), Vääräsmäki, M. (Marja), Vrijheid, M. (Martine), Ziegler, A.-G. (Anette-G.), Annesi-Maesano, I. (Isabella), Bustamante, M. (Mariona), Huang, R.-C. (Rae-Chi), Hummel, S. (Sandra), Just, A. C. (Allan C.), Kajantie, E. (Eero), Lahti, J. (Jari), Lawlor, D. (Deborah), Räikkönen, K. (Katri), Järvelin, M.-R. (Marjo-Riitta), Felix, J. F. (Janine F.), Sebert, S. (Sylvain), Ronkainen, J. (Justiina), Heiskala, A. (Anni), Vehmeijer, F. O. (Florianne O. L.), Lowry, E. (Estelle), Caramaschi, D. (Doretta), Estrada Gutierrez, G. (Guadalupe), Heiss, J. A. (Jonathan A.), Hummel, N. (Nadine), Keikkala, E. (Elina), Kvist, T. (Tuomas), Kupsco, A. (Allison), Melton, P. E. (Phillip E.), Pesce, G. (Giancarlo), Soomro, M. H. (Munawar H.), Vives-Usano, M. (Marta), Baiz, N. (Nour), Binder, E. (Elisabeth), Czamara, D. (Darina), Guxens, M. (Mònica), Mustaniemi, S. (Sanna), London, S. J. (Stephanie J.), Rauschert, S. (Sebastian), Vääräsmäki, M. (Marja), Vrijheid, M. (Martine), Ziegler, A.-G. (Anette-G.), Annesi-Maesano, I. (Isabella), Bustamante, M. (Mariona), Huang, R.-C. (Rae-Chi), Hummel, S. (Sandra), Just, A. C. (Allan C.), Kajantie, E. (Eero), Lahti, J. (Jari), Lawlor, D. (Deborah), Räikkönen, K. (Katri), Järvelin, M.-R. (Marjo-Riitta), Felix, J. F. (Janine F.), and Sebert, S. (Sylvain)
Abstract: Altered maternal haemoglobin levels during pregnancy are associated with pre-clinical and clinical conditions affecting the fetus. Evidence from animal models suggests that these associations may be partially explained by differential DNA methylation in the newborn with possible long-term consequences. To test this in humans, we meta-analyzed the epigenome-wide associations of maternal haemoglobin levels during pregnancy with offspring DNA methylation in 3,967 newborn cord blood and 1,534 children and 1,962 adolescent whole-blood samples derived from 10 cohorts. DNA methylation was measured using Illumina Infinium Methylation 450K or MethylationEPIC arrays covering 450,000 and 850,000 methylation sites, respectively. There was no statistical support for the association of maternal haemoglobin levels with offspring DNA methylation either at individual methylation sites or clustered in regions. For most participants, maternal haemoglobin levels were within the normal range in the current study, whereas adverse perinatal outcomes often arise at the extremes. Thus, this study does not rule out the possibility that associations with offspring DNA methylation might be seen in studies with more extreme maternal haemoglobin levels.
Published: 2022

34. Longitudinal associations of DNA methylation and sleep in children: a meta‑analysis

Author: Sammallahti, S., Koopman‑Verhoeff, M.E., Binter, A.-C., Mulder, R.H., Cabré‑Riera, A., Kvist, T., Malmberg, A.L.K., Pesce, G., Plancoulaine, S., Heiss, J.A., Rifas‐Shiman, S.L., Röder, Stefan, Starling, A.P., Wilson, R., Guerlich, K., Haftorn, K.L., Page, C.M., Luik, A.I., Tiemeier, H., Felix, J.F., Raikkonen, K., Lahti, J., Relton, C.L., Sharp, G.C., Waldenberger, M., Grote, V., Heude, B., Annesi‑Maesano, I., Hivert, M.-F., Zenclussen, Ana Claudia, Herberth, Gunda, Dabelea, D., Grazuleviciene, R., Vafeiadi, M., Håberg, S.E., London, S.J., Guxens, M., Richmond, R.C., Cecil, C.A.M., Sammallahti, S., Koopman‑Verhoeff, M.E., Binter, A.-C., Mulder, R.H., Cabré‑Riera, A., Kvist, T., Malmberg, A.L.K., Pesce, G., Plancoulaine, S., Heiss, J.A., Rifas‐Shiman, S.L., Röder, Stefan, Starling, A.P., Wilson, R., Guerlich, K., Haftorn, K.L., Page, C.M., Luik, A.I., Tiemeier, H., Felix, J.F., Raikkonen, K., Lahti, J., Relton, C.L., Sharp, G.C., Waldenberger, M., Grote, V., Heude, B., Annesi‑Maesano, I., Hivert, M.-F., Zenclussen, Ana Claudia, Herberth, Gunda, Dabelea, D., Grazuleviciene, R., Vafeiadi, M., Håberg, S.E., London, S.J., Guxens, M., Richmond, R.C., and Cecil, C.A.M.
Abstract: Background Sleep is important for healthy functioning in children. Numerous genetic and environmental factors, from conception onwards, may influence this phenotype. Epigenetic mechanisms such as DNA methylation have been proposed to underlie variation in sleep or may be an early-life marker of sleep disturbances. We examined if DNA methylation at birth or in school age is associated with parent-reported and actigraphy-estimated sleep outcomes in children. Methods We meta-analysed epigenome-wide association study results. DNA methylation was measured from cord blood at birth in 11 cohorts and from peripheral blood in children (4–13 years) in 8 cohorts. Outcomes included parent-reported sleep duration, sleep initiation and fragmentation problems, and actigraphy-estimated sleep duration, sleep onset latency and wake-after-sleep-onset duration. Results We found no associations between DNA methylation at birth and parent-reported sleep duration (n = 3658), initiation problems (n = 2504), or fragmentation (n = 1681) (p values above cut-off 4.0 × 10–8). Lower methylation at cg24815001 and cg02753354 at birth was associated with longer actigraphy-estimated sleep duration (p = 3.31 × 10–8, n = 577) and sleep onset latency (p = 8.8 × 10–9, n = 580), respectively. DNA methylation in childhood was not cross-sectionally associated with any sleep outcomes (n = 716–2539). Conclusion DNA methylation, at birth or in childhood, was not associated with parent-reported sleep. Associations observed with objectively measured sleep outcomes could be studied further if additional data sets become available. &nbsp
Published: 2022

35. Meta-analysis of epigenome-wide association studies in newborns and children show widespread sex differences in blood DNA methylation

Author: Universitat Rovira i Virgili, Solomon, O; Huen, K; Yousefi, P; Küpers, LK; González, JR; Suderman, M; Reese, SE; Page, CM; Gruzieva, O; Rzehak, P; Gao, L; Bakulski, KM; Novoloaca, A; Allard, C; Pappa, I; Llambrich, M; Vives, M; Jima, DD; Kvist, T; Baccarelli, A; White, C; Rezwan, FI; Sharp, GC; Tindula, G; Bergström, A; Grote, V; Dou, JF; Isaevska, E; Magnus, MC; Corpeleijn, E; Perron, P; Jaddoe, VWV; Nohr, EA; Maitre, L; Foraster, M; Hoyo, C; Håberg, SE; Lahti, J; DeMeo, DL; Zhang, HM; Karmaus, W; Kull, I; Koletzko, B; Feinberg, JI; Gagliardi, L; Bouchard, L; Ramlau-Hansen, CH; Tiemeier, H; Santorelli, G; Maguire, RL; Czamara, D; Litonjua, AA; Langhendries, JP; Plusquin, M; Lepeule, J; Binder, EB; Verduci, E; Dwyer, T; Carracedo, A; Ferre, N; Eskenazi, B; Kogevinas, M; Nawrot, TS; Munthe-Kaas, MC; Herceg, Z; Relton, C; Melén, E; Gruszfeld, D; Breton, C; Fallin, MD; Ghantous, A; Nystad, W; Heude, B; Snieder, H; Hivert, MF; Felix, JF; Sorensen, TIA; Bustamante, M; Murphy, SK; Raikkönen, K; Oken, E; Holloway, JW; Arshad, SH; London, SJ; Holland, N, Universitat Rovira i Virgili, and Solomon, O; Huen, K; Yousefi, P; Küpers, LK; González, JR; Suderman, M; Reese, SE; Page, CM; Gruzieva, O; Rzehak, P; Gao, L; Bakulski, KM; Novoloaca, A; Allard, C; Pappa, I; Llambrich, M; Vives, M; Jima, DD; Kvist, T; Baccarelli, A; White, C; Rezwan, FI; Sharp, GC; Tindula, G; Bergström, A; Grote, V; Dou, JF; Isaevska, E; Magnus, MC; Corpeleijn, E; Perron, P; Jaddoe, VWV; Nohr, EA; Maitre, L; Foraster, M; Hoyo, C; Håberg, SE; Lahti, J; DeMeo, DL; Zhang, HM; Karmaus, W; Kull, I; Koletzko, B; Feinberg, JI; Gagliardi, L; Bouchard, L; Ramlau-Hansen, CH; Tiemeier, H; Santorelli, G; Maguire, RL; Czamara, D; Litonjua, AA; Langhendries, JP; Plusquin, M; Lepeule, J; Binder, EB; Verduci, E; Dwyer, T; Carracedo, A; Ferre, N; Eskenazi, B; Kogevinas, M; Nawrot, TS; Munthe-Kaas, MC; Herceg, Z; Relton, C; Melén, E; Gruszfeld, D; Breton, C; Fallin, MD; Ghantous, A; Nystad, W; Heude, B; Snieder, H; Hivert, MF; Felix, JF; Sorensen, TIA; Bustamante, M; Murphy, SK; Raikkönen, K; Oken, E; Holloway, JW; Arshad, SH; London, SJ; Holland, N
Abstract: Background: Among children, sex-specific differences in disease prevalence, age of onset, and susceptibility have been observed in health conditions including asthma, immune response, metabolic health, some pediatric and adult cancers, and psychiatric disorders. Epigenetic modifications such as DNA methylation may play a role in the sexual differences observed in diseases and other physiological traits. Methods: We performed a meta-analysis of the association of sex and cord blood DNA methylation at over 450,000 CpG sites in 8438 newborns from 17 cohorts participating in the Pregnancy And Childhood Epigenetics (PACE) Consortium. We also examined associations of child sex with DNA methylation in older children ages 5.5–10 years from 8 cohorts (n = 4268). Results: In newborn blood, sex was associated at Bonferroni level significance with differences in DNA methylation at 46,979 autosomal CpG sites (p < 1.3 × 10−7) after adjusting for white blood cell proportions and batch. Most of those sites had lower methylation levels in males than in females. Of the differentially methylated CpG sites identified in newborn blood, 68% (31,727) met look-up level significance (p < 1.1 × 10−6) in older children and had methylation differences in the same direction. Conclusions: This is a large-scale meta-analysis examining sex differences in DNA methylation in newborns and older children. Expanding upon previous studies, we replicated previous findings and identified additional autosomal sites with sex-specific differences in DNA methylation. Differentially methylated sites were enriched in genes involved in cancer, psychiatric disorders, and cardiovascular phenotypes.
Published: 2022

36. Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption

Author: Cornelis, M C, Byrne, E M, Esko, T, Nalls, M A, Ganna, A, Paynter, N, Monda, K L, Amin, N, Fischer, K, Renstrom, F, Ngwa, J S, Huikari, V, Cavadino, A, Nolte, I M, Teumer, A, Yu, K, Marques-Vidal, P, Rawal, R, Manichaikul, A, Wojczynski, M K, Vink, J M, Zhao, J H, Burlutsky, G, Lahti, J, Mikkilä, V, Lemaitre, R N, Eriksson, J, Musani, S K, Tanaka, T, Geller, F, Luan, J, Hui, J, Mägi, R, Dimitriou, M, Garcia, M E, Ho, W-K, Wright, M J, Rose, L M, Magnusson, P K E, Pedersen, N L, Couper, D, Oostra, B A, Hofman, A, Ikram, M A, Tiemeier, H W, Uitterlinden, A G, van Rooij, F J A, Barroso, I, Johansson, I, Xue, L, Kaakinen, M, Milani, L, Power, C, Snieder, H, Stolk, R P, Baumeister, S E, Biffar, R, Gu, F, Bastardot, F, Kutalik, Z, Jacobs, Jr, D R, Forouhi, N G, Mihailov, E, Lind, L, Lindgren, C, Michaëlsson, K, Morris, A, Jensen, M, Khaw, K-T, Luben, R N, Wang, J J, Männistö, S, Perälä, M-M, Kähönen, M, Lehtimäki, T, Viikari, J, Mozaffarian, D, Mukamal, K, Psaty, B M, Döring, A, Heath, A C, Montgomery, G W, Dahmen, N, Carithers, T, Tucker, K L, Ferrucci, L, Boyd, H A, Melbye, M, Treur, J L, Mellström, D, Hottenga, J J, Prokopenko, I, Tönjes, A, Deloukas, P, Kanoni, S, Lorentzon, M, Houston, D K, Liu, Y, Danesh, J, Rasheed, A, Mason, M A, Zonderman, A B, Franke, L, Kristal, B S, Karjalainen, J, Reed, D R, Westra, H-J, Evans, M K, Saleheen, D, Harris, T B, Dedoussis, G, Curhan, G, Stumvoll, M, Beilby, J, Pasquale, L R, Feenstra, B, Bandinelli, S, Ordovas, J M, Chan, A T, Peters, U, Ohlsson, C, Gieger, C, Martin, N G, Waldenberger, M, Siscovick, D S, Raitakari, O, Eriksson, J G, Mitchell, P, Hunter, D J, Kraft, P, Rimm, E B, Boomsma, D I, Borecki, I B, Loos, R J F, Wareham, N J, Vollenweider, P, Caporaso, N, Grabe, H J, Neuhouser, M L, Wolffenbuttel, B H R, Hu, F B, Hyppönen, E, Järvelin, M-R, Cupples, L A, Franks, P W, Ridker, P M, van Duijn, C M, Heiss, G, Metspalu, A, North, K E, Ingelsson, E, Nettleton, J A, van Dam, R M, and Chasman, D I
Published: 2015
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37. CDK/CK1 inhibitors roscovitine and CR8 downregulate amplified MYCN in neuroblastoma cells

Author: Delehouzé, C, Godl, K, Loaëc, N, Bruyère, C, Desban, N, Oumata, N, Galons, H, Roumeliotis, T I, Giannopoulou, E G, Grenet, J, Twitchell, D, Lahti, J, Mouchet, N, Galibert, M-D, Garbis, S D, and Meijer, L
Published: 2014
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38. Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia: a report from the Cognitive Genomics consorTium (COGENT)

Author: Lencz, T, Knowles, E, Davies, G, Guha, S, Liewald, D C, Starr, J M, Djurovic, S, Melle, I, Sundet, K, Christoforou, A, Reinvang, I, Mukherjee, S, DeRosse, Pamela, Lundervold, A, Steen, V M, John, M, Espeseth, T, Räikkönen, K, Widen, E, Palotie, A, Eriksson, J G, Giegling, I, Konte, B, Ikeda, M, Roussos, P, Giakoumaki, S, Burdick, K E, Payton, A, Ollier, W, Horan, M, Donohoe, G, Morris, D, Corvin, A, Gill, M, Pendleton, N, Iwata, N, Darvasi, A, Bitsios, P, Rujescu, D, Lahti, J, Hellard, S L, Keller, M C, Andreassen, O A, Deary, I J, Glahn, D C, and Malhotra, A K
Published: 2014
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39. CHK2 kinase promotes pre-mRNA splicing via phosphorylating CDK11p110

Author: Choi, H-H, Choi, H-K, Jung, S Y, Hyle, J, Kim, B-J, Yoon, K, Cho, E-J, Youn, H-D, Lahti, J M, Qin, J, and Kim, S-T
Published: 2014
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40. Genome-wide association study of circulating interleukin 6 levels identifies novel loci

Author: Ahluwalia, T.S., Prins, B.P., Abdollahi, M., Armstrong, N.J., Aslibekyan, S., Bain, L., Jefferis, B., Baumert, J., Beekman, M., Ben-Shlomo, Y., Bis, J.C., Mitchell, B.D., Geus, E. de, Delgado, G.E., Marek, D., Eriksson, J., Kajantie, E., Kanoni, S., Kemp, J.P., Lu, C., Marioni, R.E., McLachlan, S., Milaneschi, Y., Nolte, I.M., Petrelis, A.M., Porcu, E., Sabater-Lleal, M., Naderi, E., Seppala, I., Shah, T., Singhal, G., Standl, M., Teumer, A., Thalamuthu, A., Thiering, E., Trompet, S., Ballantyne, C.M., Benjamin, E.J., Casas, J.P., Toben, C., Dedoussis, G., Deelen, J., Durda, P., Engmann, J., Feitosa, M.F., Grallert, H., Hammarstedt, A., Harris, S.E., Homuth, G., Hottenga, J.J., Jalkanen, S., Jamshidi, Y., Jawahar, M.C., Jess, T., Kivimaki, M., Kleber, M.E., Lahti, J., Liu, Y., Marques-Vidal, P., Mellstrom, D., Mooijaart, S.P., Muller-Nurasyid, M., Penninx, B., Revez, J.A., Rossing, P., Raikkonen, K., Sattar, N., Scharnagl, H., Sennblad, B., Silveira, A., St Pourcain, B., Timpson, N.J., Trollor, J., Dongen, J. van, Heemst, D. van, Visvikis-Siest, S., Vollenweider, P., Volker, U., Waldenberger, M., Willemsen, G., Zabaneh, D., Morris, R.W., Arnett, D.K., Baune, B.T., Boomsma, D.I., Chang, Y.P.C., Deary, I.J., Deloukas, P., Eriksson, J.G., Evans, D.M., Ferreira, M.A., Gaunt, T., Gudnason, V., Hamsten, A., Heinrich, J., Hingorani, A., Humphries, S.E., Jukema, J.W., Koenig, W., Kumari, M., Kutalik, Z., Lawlor, D.A., Lehtimaki, T., Marz, W., Mather, K.A., Naitza, S., Nauck, M., Ohlsson, C., Price, J.F., Raitakari, O., Rice, K., Sachdev, P.S., Slagboom, E., Sorensen, T.I.A., Spector, T., Stacey, D., Stathopoulou, M.G., Tanaka, T., Wannamethee, S.G., Whincup, P., Rotter, J.I., Dehghan, A., Boerwinkle, E., Psaty, B.M., Snieder, H., Alizadeh, B.Z., and CHARGE Inflammation Working Grp
Abstract: Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67428 (n(discovery)=52654 and n(replication)=14774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (P-combined=1.8x10(-11)), HLA-DRB1/DRB5 rs660895 on Chr6p21 (P-combined=1.5x10(-10)) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (P-combined=1.2x10(-122)). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.
Published: 2021

41. Genome-Wide Association Study of Circulating Interleukin 6 Levels Identifies Novel Loci

Author: Ahluwalia, TS, Prins, BP, Abdollahi, M, Armstrong, NJ, Aslibekyan, S, Bain, L, Jefferis, B, Baumert, J, Beekman, M, Ben-Shlomo, Y, Bis, JC, Mitchell, BD, de Geus, E, Delgado, GE, Marek, D, Eriksson, J, Kajantie, E, Kanoni, S, Kemp, JP, Lu, C, Marioni, RE, McLachlan, S, Milaneschi, Y, Nolte, IM, Petrelis, AM, Porcu, E, Sabater-Lleal, M, Naderi, E, Seppälä, I, Shah, T, Singhal, G, Standl, M, Teumer, A, Thalamuthu, A, Thiering, E, Trompet, S, Ballantyne, CM, Benjamin, EJ, Casas, JP, Toben, C, Dedoussis, G, Deelen, J, Durda, P, Engmann, J, Feitosa, MF, Grallert, H, Hammarstedt, A, Harris, SE, Homuth, G, Hottenga, J-J, Jalkanen, S, Jamshidi, Y, Jawahar, MC, Jess, T, Kivimaki, M, Kleber, ME, Lahti, J, Liu, Y, Marques-Vidal, P, Mellström, D, Mooijaart, SP, Müller-Nurasyid, M, Penninx, B, Revez, JA, Rossing, P, Räikkönen, K, Sattar, N, Scharnagl, H, Sennblad, B, Silveira, A, Pourcain, BS, Timpson, NJ, Trollor, J, CHARGE Inflammation Working Group, van Dongen, J, Van Heemst, D, Visvikis-Siest, S, Vollenweider, P, Völker, U, Waldenberger, M, Willemsen, G, Zabaneh, D, Morris, RW, Arnett, DK, Baune, BT, Boomsma, DI, Chang, Y-PC, Deary, IJ, Deloukas, P, Eriksson, JG, Evans, DM, Ferreira, MA, Gaunt, T, Gudnason, V, Hamsten, A, Heinrich, J, Hingorani, A, Humphries, SE, Jukema, JW, Koeing, W, Kumari, M, Kutalik, Z, Lawlor, DA, Lehtimäki, T, März, W, Mather, K, Naitza, S, Nauck, M, Ohlsson, C, Price, JF, Raitakari, O, Rice, K, Sachdev, PS, Slagboom, E, Sørensen, TIA, Spector, T, Stacey, D, Stathopoulou, MG, Tanaka, T, Wannamethee, SG, Whincup, P, Rotter, JI, Dehghan, A, Boerwinkle, E, Psaty, BM, Snieder, H, and Alizadeh, BZ
Abstract: Interleukin-6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery, and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed-effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on Chromosome (Chr) 2q14, (pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.
Published: 2021

42. TCR3: A Third T-Cell Receptor in the Chicken

Author: Chen, C. H., Sowder, J. T., Lahti, J. M., Cihak, J., Lösch, U., and Cooper, M. D.
Published: 1989

43. Two Distinct αβ T-Cell Lineages can be Distinguished by the Differential Usage of T-Cell Receptor V β Gene SegmentS

Author: Lahti, J. M., Tjoelker, L. W., Pickel, J. M., Schat, K. A., Calnek, B. W., Thompson, C. B., and Cooper, M. D.
Published: 1991

44. Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics

Author: Lam, M. Chen, C.-Y. Ge, T. Xia, Y. Hill, D.W. Trampush, J.W. Yu, J. Knowles, E. Davies, G. Stahl, E.A. Huckins, L. Liewald, D.C. Djurovic, S. Melle, I. Christoforou, A. Reinvang, I. DeRosse, P. Lundervold, A.J. Steen, V.M. Espeseth, T. Räikkönen, K. Widen, E. Palotie, A. Eriksson, J.G. Giegling, I. Konte, B. Hartmann, A.M. Roussos, P. Giakoumaki, S. Burdick, K.E. Payton, A. Ollier, W. Chiba-Falek, O. Koltai, D.C. Need, A.C. Cirulli, E.T. Voineskos, A.N. Stefanis, N.C. Avramopoulos, D. Hatzimanolis, A. Smyrnis, N. Bilder, R.M. Freimer, N.B. Cannon, T.D. London, E. Poldrack, R.A. Sabb, F.W. Congdon, E. Conley, E.D. Scult, M.A. Dickinson, D. Straub, R.E. Donohoe, G. Morris, D. Corvin, A. Gill, M. Hariri, A.R. Weinberger, D.R. Pendleton, N. Bitsios, P. Rujescu, D. Lahti, J. Le Hellard, S. Keller, M.C. Andreassen, O.A. Deary, I.J. Glahn, D.C. Huang, H. Liu, C. Malhotra, A.K. Lencz, T.
Abstract: Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify “druggable” targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing. © 2021, The Author(s).
Published: 2021

45. Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies

Author: Munn-Chernoff, M.A. Johnson, E.C. Chou, Y.-L. Coleman, J.R.I. Thornton, L.M. Walters, R.K. Yilmaz, Z. Baker, J.H. Hübel, C. Gordon, S. Medland, S.E. Watson, H.J. Gaspar, H.A. Bryois, J. Hinney, A. Leppä, V.M. Mattheisen, M. Ripke, S. Yao, S. Giusti-Rodríguez, P. Hanscombe, K.B. Adan, R.A.H. Alfredsson, L. Ando, T. Andreassen, O.A. Berrettini, W.H. Boehm, I. Boni, C. Boraska Perica, V. Buehren, K. Burghardt, R. Cassina, M. Cichon, S. Clementi, M. Cone, R.D. Courtet, P. Crow, S. Crowley, J.J. Danner, U.N. Davis, O.S.P. de Zwaan, M. Dedoussis, G. Degortes, D. DeSocio, J.E. Dick, D.M. Dikeos, D. Dina, C. Dmitrzak-Weglarz, M. Docampo, E. Duncan, L.E. Egberts, K. Ehrlich, S. Escaramís, G. Esko, T. Estivill, X. Farmer, A. Favaro, A. Fernández-Aranda, F. Fichter, M.M. Fischer, K. Föcker, M. Foretova, L. Forstner, A.J. Forzan, M. Franklin, C.S. Gallinger, S. Giegling, I. Giuranna, J. Gonidakis, F. Gorwood, P. Gratacos Mayora, M. Guillaume, S. Guo, Y. Hakonarson, H. Hatzikotoulas, K. Hauser, J. Hebebrand, J. Helder, S.G. Herms, S. Herpertz-Dahlmann, B. Herzog, W. Huckins, L.M. Hudson, J.I. Imgart, H. Inoko, H. Janout, V. Jiménez-Murcia, S. Julià, A. Kalsi, G. Kaminská, D. Karhunen, L. Karwautz, A. Kas, M.J.H. Kennedy, J.L. Keski-Rahkonen, A. Kiezebrink, K. Kim, Y.-R. Klump, K.L. Knudsen, G.P.S. La Via, M.C. Le Hellard, S. Levitan, R.D. Li, D. Lilenfeld, L. Lin, B.D. Lissowska, J. Luykx, J. Magistretti, P.J. Maj, M. Mannik, K. Marsal, S. Marshall, C.R. Mattingsdal, M. McDevitt, S. McGuffin, P. Metspalu, A. Meulenbelt, I. Micali, N. Mitchell, K. Monteleone, A.M. Monteleone, P. Nacmias, B. Navratilova, M. Ntalla, I. O'Toole, J.K. Ophoff, R.A. Padyukov, L. Palotie, A. Pantel, J. Papezova, H. Pinto, D. Rabionet, R. Raevuori, A. Ramoz, N. Reichborn-Kjennerud, T. Ricca, V. Ripatti, S. Ritschel, F. Roberts, M. Rotondo, A. Rujescu, D. Rybakowski, F. Santonastaso, P. Scherag, A. Scherer, S.W. Schmidt, U. Schork, N.J. Schosser, A. Seitz, J. Slachtova, L. Slagboom, P.E. Slof-Op't Landt, M.C.T. Slopien, A. Sorbi, S. Świątkowska, B. Szatkiewicz, J.P. Tachmazidou, I. Tenconi, E. Tortorella, A. Tozzi, F. Treasure, J. Tsitsika, A. Tyszkiewicz-Nwafor, M. Tziouvas, K. van Elburg, A.A. van Furth, E.F. Wagner, G. Walton, E. Widen, E. Zeggini, E. Zerwas, S. Zipfel, S. Bergen, A.W. Boden, J.M. Brandt, H. Crawford, S. Halmi, K.A. Horwood, L.J. Johnson, C. Kaplan, A.S. Kaye, W.H. Mitchell, J. Olsen, C.M. Pearson, J.F. Pedersen, N.L. Strober, M. Werge, T. Whiteman, D.C. Woodside, D.B. Grove, J. Henders, A.K. Larsen, J.T. Parker, R. Petersen, L.V. Jordan, J. Kennedy, M.A. Birgegård, A. Lichtenstein, P. Norring, C. Landén, M. Mortensen, P.B. Polimanti, R. McClintick, J.N. Adkins, A.E. Aliev, F. Bacanu, S.-A. Batzler, A. Bertelsen, S. Biernacka, J.M. Bigdeli, T.B. Chen, L.-S. Clarke, T.-K. Degenhardt, F. Docherty, A.R. Edwards, A.C. Foo, J.C. Fox, L. Frank, J. Hack, L.M. Hartmann, A.M. Hartz, S.M. Heilmann-Heimbach, S. Hodgkinson, C. Hoffmann, P. Hottenga, J.-J. Konte, B. Lahti, J. Lahti-Pulkkinen, M. Lai, D. Ligthart, L. Loukola, A. Maher, B.S. Mbarek, H. McIntosh, A.M. McQueen, M.B. Meyers, J.L. Milaneschi, Y. Palviainen, T. Peterson, R.E. Ryu, E. Saccone, N.L. Salvatore, J.E. Sanchez-Roige, S. Schwandt, M. Sherva, R. Streit, F. Strohmaier, J. Thomas, N. Wang, J.-C. Webb, B.T. Wedow, R. Wetherill, L. Wills, A.G. Zhou, H. Boardman, J.D. Chen, D. Choi, D.-S. Copeland, W.E. Culverhouse, R.C. Dahmen, N. Degenhardt, L. Domingue, B.W. Frye, M.A. Gäebel, W. Hayward, C. Ising, M. Keyes, M. Kiefer, F. Koller, G. Kramer, J. Kuperman, S. Lucae, S. Lynskey, M.T. Maier, W. Mann, K. Männistö, S. Müller-Myhsok, B. Murray, A.D. Nurnberger, J.I. Preuss, U. Räikkönen, K. Reynolds, M.D. Ridinger, M. Scherbaum, N. Schuckit, M.A. Soyka, M. Treutlein, J. Witt, S.H. Wodarz, N. Zill, P. Adkins, D.E. Boomsma, D.I. Bierut, L.J. Brown, S.A. Bucholz, K.K. Costello, E.J. de Wit, H. Diazgranados, N. Eriksson, J.G. Farrer, L.A. Foroud, T.M. Gillespie, N.A. Goate, A.M. Goldman, D. Grucza, R.A. Hancock, D.B. Harris, K.M. Hesselbrock, V. Hewitt, J.K. Hopfer, C.J. Iacono, W.G. Johnson, E.O. Karpyak, V.M. Kendler, K.S. Kranzler, H.R. Krauter, K. Lind, P.A. McGue, M. MacKillop, J. Madden, P.A.F. Maes, H.H. Magnusson, P.K.E. Nelson, E.C. Nöthen, M.M. Palmer, A.A. Penninx, B.W.J.H. Porjesz, B. Rice, J.P. Rietschel, M. Riley, B.P. Rose, R.J. Shen, P.-H. Silberg, J. Stallings, M.C. Tarter, R.E. Vanyukov, M.M. Vrieze, S. Wall, T.L. Whitfield, J.B. Zhao, H. Neale, B.M. Wade, T.D. Heath, A.C. Montgomery, G.W. Martin, N.G. Sullivan, P.F. Kaprio, J. Breen, G. Gelernter, J. Edenberg, H.J. Bulik, C.M. Agrawal, A.
Subjects: mental disorders
Abstract: Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [rg], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (rg = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (rg = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (rg = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (rgs = −0.19 to −0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors. © 2020 Society for the Study of Addiction
Published: 2021

46. DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan

Author: Dongen, J. Van, Hagenbeek, F.A., Suderman, M., Roetman, P.J., Sugden, K., Chiocchetti, A.G., Ismail, K., Mulder, R.H., Hafferty, J.D., Adams, M.J., Walker, R.M., Morris, S.W., Lahti, J., Küpers, L.K., Escaramis, G., Alemany, S., Bonder, M. Jan, Meijer, M., Ip, H.F., Jansen, R., Baselmans, B.M.L., Parmar, P., Lowry, E., Streit, F., Sirignano, L., Send, T.S., Frank, J., Jylhävä, J., Wang, Y., Mishra, P.P., Colins, O.F., Corcoran, D.L., Poulton, R., Mill, J., Hannon, E., Arseneault, L., Korhonen, T., Vuoksimaa, E., Felix, J.F., Bakermans-Kranenburg, M.J., Campbell, A., Czamara, D., Binder, E., Corpeleijn, E., Gonzalez, J.R., Grazuleviciene, R., Gutzkow, K.B., Evandt, J., Vafeiadi, M., Klein, M., Meer, D. van der, Ligthart, L., Kluft, C., Davies, G.E., Hakulinen, C., Keltikangas-Järvinen, L., Franke, B., Freitag, C.M., Konrad, K., Hervas, A., Fernández-Rivas, A., Vetro, A., Raitakari, O., Lehtimäki, T., Vermeiren, R., Strandberg, T., Räikkönen, K., Snieder, H., Witt, S.H., Deuschle, M., Pedersen, N.L., Hägg, S., Sunyer, J., Franke, L., Kaprio, J., Ollikainen, M., Moffitt, T.E., Tiemeier, H., van, I.M.H., Relton, C., Vrijheid, M., Sebert, S., Jarvelin, M.R., Caspi, A., Evans, K.L., McIntosh, A.M., Bartels, M., Boomsma, D.I., Dongen, J. Van, Hagenbeek, F.A., Suderman, M., Roetman, P.J., Sugden, K., Chiocchetti, A.G., Ismail, K., Mulder, R.H., Hafferty, J.D., Adams, M.J., Walker, R.M., Morris, S.W., Lahti, J., Küpers, L.K., Escaramis, G., Alemany, S., Bonder, M. Jan, Meijer, M., Ip, H.F., Jansen, R., Baselmans, B.M.L., Parmar, P., Lowry, E., Streit, F., Sirignano, L., Send, T.S., Frank, J., Jylhävä, J., Wang, Y., Mishra, P.P., Colins, O.F., Corcoran, D.L., Poulton, R., Mill, J., Hannon, E., Arseneault, L., Korhonen, T., Vuoksimaa, E., Felix, J.F., Bakermans-Kranenburg, M.J., Campbell, A., Czamara, D., Binder, E., Corpeleijn, E., Gonzalez, J.R., Grazuleviciene, R., Gutzkow, K.B., Evandt, J., Vafeiadi, M., Klein, M., Meer, D. van der, Ligthart, L., Kluft, C., Davies, G.E., Hakulinen, C., Keltikangas-Järvinen, L., Franke, B., Freitag, C.M., Konrad, K., Hervas, A., Fernández-Rivas, A., Vetro, A., Raitakari, O., Lehtimäki, T., Vermeiren, R., Strandberg, T., Räikkönen, K., Snieder, H., Witt, S.H., Deuschle, M., Pedersen, N.L., Hägg, S., Sunyer, J., Franke, L., Kaprio, J., Ollikainen, M., Moffitt, T.E., Tiemeier, H., van, I.M.H., Relton, C., Vrijheid, M., Sebert, S., Jarvelin, M.R., Caspi, A., Evans, K.L., McIntosh, A.M., Bartels, M., and Boomsma, D.I.
Abstract: Item does not contain fulltext, DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10(-7); Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3-82%) of the aggression-methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.
Published: 2021

47. DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan

Author: Dongen, J. (Jenny) van, Hagenbeek, F.A. (Fiona A.), Suderman, M.J. (Matthew J.), Roetman, P.J. (Peter J.), Sugden, K. (Karen), Chiocchetti, A.G. (Andreas G.), Ismail, K. (Khadeeja), Mulder, R.H. (Rosa), Hafferty, J.D. (Jonathan D.), Adams, M.J. (Mark J.), Walker, R.M. (Rosie M.), Morris, S.W. (Stewart W.), Lahti, J. (Jari), Küpers, A.M. (Marlijn), Escaramis, G. (Georgia), Alemany, S. (Silvia), Jan Bonder, M. (Marc), Meijer, M. (Mandy), Ip, H.F. (Hill F.), Jansen, R. (Rick), Baselmans, B.M.L. (Bart M. L.), Parmar, P. (Priyanka), Lowry, E. (Estelle), Streit, F. (Fabian), Sirignano, L. (Lea), Send, T.S. (Tabea S.), Frank, J. (Josef), Jylhävä, J. (Juulia), Wang, Y. (Yunzhang), Mishra, P.P. (Pashupati Prasad), Colins, O.F. (Olivier F.), Corcoran, D.L. (David L.), Poulton, R. (Richie), Mill, J. (Jonathan), Hannon, E. (Eilis), Arseneault, L. (Louise), Korhonen, T. (Tellervo), Vuoksimaa, E. (Eero), Felix, J.F. (Janine), Bakermans-Kranenburg, M.J. (Marian), Campbell, A. (Archie), Czamara, D. (Darina), Binder, E.B. (Elisabeth), Corpeleijn, E. (Eva), Gonzalez, J.R. (Juan R.), Grazuleviciene, R. (Regina), Gutzkow, K.B. (Kristine B.), Evandt, J. (Jorunn), Vafeiadi, M. (Marina), Klein, M. (Marieke), van der Meer, D. (Dennis), Ligthart, L. (Lannie), Kluft, C. (Cornelis), Davies, G.E. (Gareth E.), Hakulinen, C. (Christian), Keltikangas-Järvinen, L. (Liisa), Franke, B. (Barbara), Freitag, C.M. (Christine), Konrad, K. (Kerstin), Hervas, A. (Amaia), Fernández-Rivas, A. (Aranzazu), Vetro, A. (Agnes), Raitakari, O. (Olli), Lehtimäki, T. (Terho), Vermeiren, R.R.J.M. (Robert R.J.M.), Strandberg, T. (Timo), Räikkönen, K. (Katri), Snieder, H. (Harold), Witt, S.H. (Stephanie H), Deuschle, M. (Michael), Pedersen, N.L. (Nancy), Hägg, S. (Sara), Sunyer, J. (Jordi), Franke, L. (Lude), Kaprio, J. (Jaakko), Ollikainen, M. (Miina), Moffitt, T.E. (Terrie E.), Tiemeier, H.W. (Henning), IJzendoorn, M.H. (Rien) van, Relton, C.L. (Caroline), Vrijheid, M. (Martine), Sebert, S. (Sylvain), Jarvelin, M.-R. (Marjo-Riitta), Caspi, A. (Avshalom), Evans, K.L. (Kathryn L.), McIntosh, A.M. (Andrew), Bartels, M. (Meike), Boomsma, D.I. (Dorret I.), Dongen, J. (Jenny) van, Hagenbeek, F.A. (Fiona A.), Suderman, M.J. (Matthew J.), Roetman, P.J. (Peter J.), Sugden, K. (Karen), Chiocchetti, A.G. (Andreas G.), Ismail, K. (Khadeeja), Mulder, R.H. (Rosa), Hafferty, J.D. (Jonathan D.), Adams, M.J. (Mark J.), Walker, R.M. (Rosie M.), Morris, S.W. (Stewart W.), Lahti, J. (Jari), Küpers, A.M. (Marlijn), Escaramis, G. (Georgia), Alemany, S. (Silvia), Jan Bonder, M. (Marc), Meijer, M. (Mandy), Ip, H.F. (Hill F.), Jansen, R. (Rick), Baselmans, B.M.L. (Bart M. L.), Parmar, P. (Priyanka), Lowry, E. (Estelle), Streit, F. (Fabian), Sirignano, L. (Lea), Send, T.S. (Tabea S.), Frank, J. (Josef), Jylhävä, J. (Juulia), Wang, Y. (Yunzhang), Mishra, P.P. (Pashupati Prasad), Colins, O.F. (Olivier F.), Corcoran, D.L. (David L.), Poulton, R. (Richie), Mill, J. (Jonathan), Hannon, E. (Eilis), Arseneault, L. (Louise), Korhonen, T. (Tellervo), Vuoksimaa, E. (Eero), Felix, J.F. (Janine), Bakermans-Kranenburg, M.J. (Marian), Campbell, A. (Archie), Czamara, D. (Darina), Binder, E.B. (Elisabeth), Corpeleijn, E. (Eva), Gonzalez, J.R. (Juan R.), Grazuleviciene, R. (Regina), Gutzkow, K.B. (Kristine B.), Evandt, J. (Jorunn), Vafeiadi, M. (Marina), Klein, M. (Marieke), van der Meer, D. (Dennis), Ligthart, L. (Lannie), Kluft, C. (Cornelis), Davies, G.E. (Gareth E.), Hakulinen, C. (Christian), Keltikangas-Järvinen, L. (Liisa), Franke, B. (Barbara), Freitag, C.M. (Christine), Konrad, K. (Kerstin), Hervas, A. (Amaia), Fernández-Rivas, A. (Aranzazu), Vetro, A. (Agnes), Raitakari, O. (Olli), Lehtimäki, T. (Terho), Vermeiren, R.R.J.M. (Robert R.J.M.), Strandberg, T. (Timo), Räikkönen, K. (Katri), Snieder, H. (Harold), Witt, S.H. (Stephanie H), Deuschle, M. (Michael), Pedersen, N.L. (Nancy), Hägg, S. (Sara), Sunyer, J. (Jordi), Franke, L. (Lude), Kaprio, J. (Jaakko), Ollikainen, M. (Miina), Moffitt, T.E. (Terrie E.), Tiemeier, H.W. (Henning), IJzendoorn, M.H. (Rien) van, Relton, C.L. (Caroline), Vrijheid, M. (Martine), Sebert, S. (Sylvain), Jarvelin, M.-R. (Marjo-Riitta), Caspi, A. (Avshalom), Evans, K.L. (Kathryn L.), McIntosh, A.M. (Andrew), Bartels, M. (Meike), and Boomsma, D.I. (Dorret I.)
Abstract: DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10−7; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48
Published: 2021
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48. Maternal haemoglobin levels in pregnancy and child DNA methylation: a study in the pregnancy and childhood epigenetics consortium

Author: Ronkainen, J. (Justiina), Heiskala, A. (Anni), Vehmeijer, F.O.L. (Florianne O.L.), Lowry, E. (Estelle), Caramaschi, D. (Doretta), Estrada Gutierrez, G. (Guadalupe), Heiss, J.A. (Jonathan A.), Hummel, N. (Nadine), Keikkala, E. (Elina), Kvist, T. (Tuomas), Kupsco, A. (Allison), Melton, P.E. (Phillip E.), Pesce, G. (Giancarlo), Soomro, M.H. (Munawar H.), Vives-Usano, M. (Marta), Baïz, N. (Nour), Binder, E.B. (Elisabeth), Czamara, D. (Darina), Guxens Junyent, M. (Mònica), Mustaniemi, S. (Sanna), London, S.J. (Stephanie J.), Rauschert, S. (Sebastian), Vääräsmäki, M. (Marja), Vrijheid, M. (Martine), Ziegler, A.-G. (Anette-G.), Annesi-Maesano, I. (Isabella), Bustamante, M. (Mariona), Huang, R.-C. (Rae-Chi), Hummel, S. (Sandra), Just, A.C. (Allan C.), Kajantie, E. (Eero), Lahti, J. (Jari), Lawlor, D. (Deborah), Räikkönen, K. (Katri), Järvelin, M.-R. (Marjo-Riitta), Felix, J.F. (Janine), Sebert, S. (Sylvain), Ronkainen, J. (Justiina), Heiskala, A. (Anni), Vehmeijer, F.O.L. (Florianne O.L.), Lowry, E. (Estelle), Caramaschi, D. (Doretta), Estrada Gutierrez, G. (Guadalupe), Heiss, J.A. (Jonathan A.), Hummel, N. (Nadine), Keikkala, E. (Elina), Kvist, T. (Tuomas), Kupsco, A. (Allison), Melton, P.E. (Phillip E.), Pesce, G. (Giancarlo), Soomro, M.H. (Munawar H.), Vives-Usano, M. (Marta), Baïz, N. (Nour), Binder, E.B. (Elisabeth), Czamara, D. (Darina), Guxens Junyent, M. (Mònica), Mustaniemi, S. (Sanna), London, S.J. (Stephanie J.), Rauschert, S. (Sebastian), Vääräsmäki, M. (Marja), Vrijheid, M. (Martine), Ziegler, A.-G. (Anette-G.), Annesi-Maesano, I. (Isabella), Bustamante, M. (Mariona), Huang, R.-C. (Rae-Chi), Hummel, S. (Sandra), Just, A.C. (Allan C.), Kajantie, E. (Eero), Lahti, J. (Jari), Lawlor, D. (Deborah), Räikkönen, K. (Katri), Järvelin, M.-R. (Marjo-Riitta), Felix, J.F. (Janine), and Sebert, S. (Sylvain)
Abstract: Altered maternal haemoglobin levels during pregnancy are associated with pre-clinical and clinical conditions affecting the fetus. Evidence from animal models suggests that these associations may be partially explained by differential DNA methylation in the newborn with possible long-term consequences. To test this in humans, we meta-analyzed the epigenome-wide associations of maternal haemoglobin levels during pregnancy with offspring DNA methylation in 3,967 newborn cord blood and 1,534 children and 1,962 adolescent whole-blood samples derived from 10 cohorts. DNA methylation was measured using Illumina Infinium Methylation 450K or MethylationEPIC arrays covering 450,000 and 850,000 methylation sites, respectively. There was no statistical support for the association of maternal haemoglobin levels with offspring DNA methylation either at individual methylation sites or clustered in regions. For most participants, maternal haemoglobin levels were within the normal range in the current study, whereas adverse perinatal outcomes often arise at the extremes. Thus, this study does not rule out the possibility that associations with offspring DNA methylation might be seen in studies with more extreme maternal haemoglobin levels.
Published: 2021
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49. DNA methylation signatures of aggression and closely related constructs:a meta-analysis of epigenome-wide studies across the lifespan

Author: van Dongen, J. (Jenny), Hagenbeek, F. A. (Fiona A.), Suderman, M. (Matthew), Roetman, P. J. (Peter J.), Sugden, K. (Karen), Chiocchetti, A. G. (Andreas G.), Ismail, K. (Khadeeja), Mulder, R. H. (Rosa H.), Hafferty, J. D. (Jonathan D.), Adams, M. J. (Mark J.), Walker, R. M. (Rosie M.), Morris, S. W. (Stewart W.), Lahti, J. (Jari), Kupers, L. K. (Leanne K.), Escaramis, G. (Georgia), Alemany, S. (Silvia), Bonder, M. J. (Marc Jan), Meijer, M. (Mandy), Ip, H. F. (Hill F.), Jansen, R. (Rick), Baselmans, B. M. (Bart M. L.), Parmar, P. (Priyanka), Lowry, E. (Estelle), Streit, F. (Fabian), Sirignano, L. (Lea), Send, T. S. (Tabea S.), Frank, J. (Josef), Jylhava, J. (Juulia), Wang, Y. (Yunzhang), Mishra, P. P. (Pashupati Prasad), Colins, O. F. (Olivier F.), Corcoran, D. L. (David L.), Poulton, R. (Richie), Mill, J. (Jonathan), Hannon, E. (Eilis), Arseneault, L. (Louise), Korhonen, T. (Tellervo), Vuoksimaa, E. (Eero), Felix, J. F. (Janine F.), Bakermans-Kranenburg, M. J. (Marian J.), Campbell, A. (Archie), Czamara, D. (Darina), Binder, E. (Elisabeth), Corpeleijn, E. (Eva), Gonzalez, J. R. (Juan R.), Grazuleviciene, R. (Regina), Gutzkow, K. B. (Kristine B.), Evandt, J. (Jorunn), Vafeiadi, M. (Marina), Klein, M. (Marieke), van der Meer, D. (Dennis), Ligthart, L. (Lannie), Kluft, C. (Cornelis), Davies, G. E. (Gareth E.), Hakulinen, C. (Christian), Keltikangas-Jarvinen, L. (Liisa), Franke, B. (Barbara), Freitag, C. M. (Christine M.), Konrad, K. (Kerstin), Hervas, A. (Amaia), Fernandez-Rivas, A. (Aranzazu), Vetro, A. (Agnes), Raitakari, O. (Olli), Lehtimaki, T. (Terho), Vermeiren, R. (Robert), Strandberg, T. (Timo), Raikkonen, K. (Katri), Snieder, H. (Harold), Witt, S. H. (Stephanie H.), Deuschle, M. (Michael), Pedersen, N. L. (Nancy L.), Hagg, S. (Sara), Sunyer, J. (Jordi), Franke, L. (Lude), Kaprio, J. (Jaakko), Ollikainen, M. (Miina), Moffitt, T. E. (Terrie E.), Tiemeier, H. (Henning), van IJzendoorn, M. H. (Marinus H.), Relton, C. (Caroline), Vrijheid, M. (Martine), Sebert, S. (Sylvain), Järvelin, M.-R. (Marjo-Riitta), Caspi, A. (Avshalom), Evans, K. L. (Kathryn L.), McIntosh, A. M. (Andrew M.), Bartels, M. (Meike), Boomsma, D. I. (Dorret, I), van Dongen, J. (Jenny), Hagenbeek, F. A. (Fiona A.), Suderman, M. (Matthew), Roetman, P. J. (Peter J.), Sugden, K. (Karen), Chiocchetti, A. G. (Andreas G.), Ismail, K. (Khadeeja), Mulder, R. H. (Rosa H.), Hafferty, J. D. (Jonathan D.), Adams, M. J. (Mark J.), Walker, R. M. (Rosie M.), Morris, S. W. (Stewart W.), Lahti, J. (Jari), Kupers, L. K. (Leanne K.), Escaramis, G. (Georgia), Alemany, S. (Silvia), Bonder, M. J. (Marc Jan), Meijer, M. (Mandy), Ip, H. F. (Hill F.), Jansen, R. (Rick), Baselmans, B. M. (Bart M. L.), Parmar, P. (Priyanka), Lowry, E. (Estelle), Streit, F. (Fabian), Sirignano, L. (Lea), Send, T. S. (Tabea S.), Frank, J. (Josef), Jylhava, J. (Juulia), Wang, Y. (Yunzhang), Mishra, P. P. (Pashupati Prasad), Colins, O. F. (Olivier F.), Corcoran, D. L. (David L.), Poulton, R. (Richie), Mill, J. (Jonathan), Hannon, E. (Eilis), Arseneault, L. (Louise), Korhonen, T. (Tellervo), Vuoksimaa, E. (Eero), Felix, J. F. (Janine F.), Bakermans-Kranenburg, M. J. (Marian J.), Campbell, A. (Archie), Czamara, D. (Darina), Binder, E. (Elisabeth), Corpeleijn, E. (Eva), Gonzalez, J. R. (Juan R.), Grazuleviciene, R. (Regina), Gutzkow, K. B. (Kristine B.), Evandt, J. (Jorunn), Vafeiadi, M. (Marina), Klein, M. (Marieke), van der Meer, D. (Dennis), Ligthart, L. (Lannie), Kluft, C. (Cornelis), Davies, G. E. (Gareth E.), Hakulinen, C. (Christian), Keltikangas-Jarvinen, L. (Liisa), Franke, B. (Barbara), Freitag, C. M. (Christine M.), Konrad, K. (Kerstin), Hervas, A. (Amaia), Fernandez-Rivas, A. (Aranzazu), Vetro, A. (Agnes), Raitakari, O. (Olli), Lehtimaki, T. (Terho), Vermeiren, R. (Robert), Strandberg, T. (Timo), Raikkonen, K. (Katri), Snieder, H. (Harold), Witt, S. H. (Stephanie H.), Deuschle, M. (Michael), Pedersen, N. L. (Nancy L.), Hagg, S. (Sara), Sunyer, J. (Jordi), Franke, L. (Lude), Kaprio, J. (Jaakko), Ollikainen, M. (Miina), Moffitt, T. E. (Terrie E.), Tiemeier, H. (Henning), van IJzendoorn, M. H. (Marinus H.), Relton, C. (Caroline), Vrijheid, M. (Martine), Sebert, S. (Sylvain), Järvelin, M.-R. (Marjo-Riitta), Caspi, A. (Avshalom), Evans, K. L. (Kathryn L.), McIntosh, A. M. (Andrew M.), Bartels, M. (Meike), and Boomsma, D. I. (Dorret, I)
Abstract: DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10−7; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3–82%) of the aggression–methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.
Published: 2021

50. The relationship between health-related quality of life and melancholic depressive symptoms is modified by brain insulin receptor gene network

Author: Selenius, J. S. (Jannica S.), Silveira, P. P. (Patricia P.), Salonen, M. (Minna), Kautiainen, H. (Hannu), von Bonsdorff, M. (Mikaela), Kajantie, E. (Eero), Lahti, J. (Jari), Eriksson, J. G. (Johan G.), Wasenius, N. S. (Niko S.), Selenius, J. S. (Jannica S.), Silveira, P. P. (Patricia P.), Salonen, M. (Minna), Kautiainen, H. (Hannu), von Bonsdorff, M. (Mikaela), Kajantie, E. (Eero), Lahti, J. (Jari), Eriksson, J. G. (Johan G.), and Wasenius, N. S. (Niko S.)
Abstract: To investigate whether expression-based polygenic risk scores for the insulin receptor gene network (ePRS-IRs) modifiy the association between type of depressive symptoms and health-related quality of life (HRQoL). This cross-sectional study includes 1558 individuals from the Helsinki Birth Cohort Study. Between 2001 and 2004, the Short Form-36 questionnaire was employed to assess mental and physical components of HRQoL and Beck Depression Inventory (BDI) to assess depressive symptoms. Depressive symptoms were categorized into minimal (BDI < 10), non-melancholic and melancholic types of depression. The ePRS-IRs were calculated for the hippocampal (hePRS-IR) and the mesocorticolimbic (mePRS-IR) regions of the brain. General linear regression models adjusted for age, sex, population stratification, lifestyle factors and body mass index were applied to analyze the data. Both types of depressive symptoms were associated with lower HRQoL (p < 0.0001). HePRS-IR modified the association between the types of depression and mental HRQoL (p for interaction = 0.005). Melancholic type of depressive symptoms was associated with higher mental HRQoL compared to the non-melancholic symptoms among individuals with low hePRS-IR (adjusted mean 4.1, 95% CI 0.7–7.4, p = 0.018). However, no such difference was evident in moderate or high hePRS-IR groups as higher hePRS-IR was associated with lower mental HRQoL (B = − 3.4, 95% CI − 5.6 to − 1.2) in individuals with melancholic type of depressive symptoms. No direct associations were detected between the ePRS-IRs and type of depressive symptoms or HRQoL. Variations in the glucose-insulin metabolism can lower HRQoL in individuals with melancholic depressive symptoms.
Published: 2021

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