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1. DIXDC1 contributes to psychiatric susceptibility by regulating dendritic spine and glutamatergic synapse density via GSK3 and Wnt/β-catenin signaling

Author: Martin, P-M, Stanley, RE, Ross, AP, Freitas, AE, Moyer, CE, Brumback, AC, Iafrati, J, Stapornwongkul, KS, Dominguez, S, Kivimäe, S, Mulligan, KA, Pirooznia, M, McCombie, WR, Potash, JB, Zandi, PP, Purcell, SM, Sanders, SJ, Zuo, Y, Sohal, VS, and Cheyette, BNR
Subjects: Biological Psychology, Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Psychology, Mental Illness, Depression, Serious Mental Illness, Neurosciences, Behavioral and Social Science, Brain Disorders, Mental Health, 2.1 Biological and endogenous factors, Mental health, Animals, Anxiety, Anxiety Disorders, Dendritic Spines, Depressive Disorder, Glutamate Plasma Membrane Transport Proteins, Glycogen Synthase Kinase 3, Intracellular Signaling Peptides and Proteins, Mental Disorders, Mice, Mice, Knockout, Polymorphism, Single Nucleotide, Pyramidal Cells, Social Behavior, Synapses, Wnt Signaling Pathway, beta Catenin, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Biological psychology, Clinical and health psychology
Abstract: Mice lacking DIX domain containing-1 (DIXDC1), an intracellular Wnt/β-catenin signal pathway protein, have abnormal measures of anxiety, depression and social behavior. Pyramidal neurons in these animals' brains have reduced dendritic spines and glutamatergic synapses. Treatment with lithium or a glycogen synthase kinase-3 (GSK3) inhibitor corrects behavioral and neurodevelopmental phenotypes in these animals. Analysis of DIXDC1 in over 9000 cases of autism, bipolar disorder and schizophrenia reveals higher rates of rare inherited sequence-disrupting single-nucleotide variants (SNVs) in these individuals compared with psychiatrically unaffected controls. Many of these SNVs alter Wnt/β-catenin signaling activity of the neurally predominant DIXDC1 isoform; a subset that hyperactivate this pathway cause dominant neurodevelopmental effects. We propose that rare missense SNVs in DIXDC1 contribute to psychiatric pathogenesis by reducing spine and glutamatergic synapse density downstream of GSK3 in the Wnt/β-catenin pathway.
Published: 2018

2. Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder.

Author: Charney, AW, Ruderfer, DM, Stahl, EA, Moran, JL, Chambert, K, Belliveau, RA, Forty, L, Gordon-Smith, K, Di Florio, A, Lee, PH, Bromet, EJ, Buckley, PF, Escamilla, MA, Fanous, AH, Fochtmann, LJ, Lehrer, DS, Malaspina, D, Marder, SR, Morley, CP, Nicolini, H, Perkins, DO, Rakofsky, JJ, Rapaport, MH, Medeiros, H, Sobell, JL, Green, EK, Backlund, L, Bergen, SE, Juréus, A, Schalling, M, Lichtenstein, P, Roussos, P, Knowles, JA, Jones, I, Jones, LA, Hultman, CM, Perlis, RH, Purcell, SM, McCarroll, SA, Pato, CN, Pato, MT, Craddock, N, Landén, M, Smoller, JW, and Sklar, P
Subjects: Chromosomes, Human, Pair 10, Humans, Aminopeptidases, Ankyrins, Calmodulin-Binding Proteins, Calcium Channels, L-Type, Cytoskeletal Proteins, Nerve Tissue Proteins, Nuclear Proteins, Case-Control Studies, Bipolar Disorder, Psychotic Disorders, Genotype, Phenotype, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Chromosomes, Human, Pair 10, Calcium Channels, L-Type, Polymorphism, Single Nucleotide, Clinical Sciences, Public Health and Health Services, Psychology
Abstract: We performed a genome-wide association study of 6447 bipolar disorder (BD) cases and 12 639 controls from the International Cohort Collection for Bipolar Disorder (ICCBD). Meta-analysis was performed with prior results from the Psychiatric Genomics Consortium Bipolar Disorder Working Group for a combined sample of 13 902 cases and 19 279 controls. We identified eight genome-wide significant, associated regions, including a novel associated region on chromosome 10 (rs10884920; P=3.28 × 10-8) that includes the brain-enriched cytoskeleton protein adducin 3 (ADD3), a non-coding RNA, and a neuropeptide-specific aminopeptidase P (XPNPEP1). Our large sample size allowed us to test the heritability and genetic correlation of BD subtypes and investigate their genetic overlap with schizophrenia and major depressive disorder. We found a significant difference in heritability of the two most common forms of BD (BD I SNP-h2=0.35; BD II SNP-h2=0.25; P=0.02). The genetic correlation between BD I and BD II was 0.78, whereas the genetic correlation was 0.97 when BD cohorts containing both types were compared. In addition, we demonstrated a significantly greater load of polygenic risk alleles for schizophrenia and BD in patients with BD I compared with patients with BD II, and a greater load of schizophrenia risk alleles in patients with the bipolar type of schizoaffective disorder compared with patients with either BD I or BD II. These results point to a partial difference in the genetic architecture of BD subtypes as currently defined.
Published: 2017

3. Analysis of exome sequence in 604 trios for recessive genotypes in schizophrenia.

Author: Rees, E, Kirov, G, Walters, JT, Richards, AL, Howrigan, D, Kavanagh, DH, Pocklington, AJ, Fromer, M, Ruderfer, DM, Georgieva, L, Carrera, N, Gormley, P, Palta, P, Williams, H, Dwyer, S, Johnson, JS, Roussos, P, Barker, DD, Banks, E, Milanova, V, Rose, SA, Chambert, K, Mahajan, M, Scolnick, EM, Moran, JL, Tsuang, MT, Glatt, SJ, Chen, WJ, Hwu, H-G, Taiwanese Trios Exome Sequencing Consortium, Neale, BM, Palotie, A, Sklar, P, Purcell, SM, McCarroll, SA, Holmans, P, Owen, MJ, and O'Donovan, MC
Subjects: Taiwanese Trios Exome Sequencing Consortium, Humans, Genetic Predisposition to Disease, Case-Control Studies, Family, Schizophrenia, Gene Frequency, Genotype, Heterozygote, Homozygote, Genes, Recessive, Female, Male, Exome, Voltage-Gated Sodium Channels, Genes, Recessive, Clinical Sciences, Public Health and Health Services, Psychology
Abstract: Genetic associations involving both rare and common alleles have been reported for schizophrenia but there have been no systematic scans for rare recessive genotypes using fully phased trio data. Here, we use exome sequencing in 604 schizophrenia proband-parent trios to investigate the role of recessive (homozygous or compound heterozygous) nonsynonymous genotypes in the disorder. The burden of recessive genotypes was not significantly increased in probands at either a genome-wide level or in any individual gene after adjustment for multiple testing. At a system level, probands had an excess of nonsynonymous compound heterozygous genotypes (minor allele frequency, MAF ⩽ 1%) in voltage-gated sodium channels (VGSCs; eight in probands and none in parents, P = 1.5 × 10(-)(4)). Previous findings of multiple de novo loss-of-function mutations in this gene family, particularly SCN2A, in autism and intellectual disability provide biological and genetic plausibility for this finding. Pointing further to the involvement of VGSCs in schizophrenia, we found that these genes were enriched for nonsynonymous mutations (MAF ⩽ 0.1%) in cases genotyped using an exome array, (5585 schizophrenia cases and 8103 controls), and that in the trios data, synaptic proteins interacting with VGSCs were also enriched for both compound heterozygosity (P = 0.018) and de novo mutations (P = 0.04). However, we were unable to replicate the specific association with compound heterozygosity at VGSCs in an independent sample of Taiwanese schizophrenia trios (N = 614). We conclude that recessive genotypes do not appear to make a substantial contribution to schizophrenia at a genome-wide level. Although multiple lines of evidence, including several from this study, suggest that rare mutations in VGSCs contribute to the disorder, in the absence of replication of the original findings regarding compound heterozygosity, this conclusion requires evaluation in a larger sample of trios.
Published: 2015

4. Mapping Typical and Altered Neurodevelopment with Sleep Macro- and Micro-Architecture

Author: Kozhemiako, N, primary, Buckley, AW, additional, Chervin, RD, additional, Redline, S, additional, and Purcell, SM, additional
Published: 2022
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5. Sources of variation in the spectral slope of the sleep EEG

Author: Kozhemiako, N, primary, Mylonas, D, additional, Pan, JQ, additional, Prerau, MJ, additional, Redline, S, additional, and Purcell, SM, additional
Published: 2021
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6. GWA study data mining and independent replication identify cardiomyopathy-associated 5 (CMYA5) as a risk gene for schizophrenia

Author: Chen, X, Lee, G, Maher, BS, Fanous, AH, Chen, J, Zhao, Z, Guo, A, van den Oord, E, Sullivan, PF, Shi, J, Levinson, DF, Gejman, PV, Sanders, A, Duan, J, Owen, MJ, Craddock, NJ, OʼDonovan, MC, Blackman, J, Lewis, D, Kirov, GK, Qin, W, Schwab, S, Wildenauer, D, Chowdari, K, Nimgaonkar, V, Straub, RE, Weinberger, DR, OʼNeill, FA, Walsh, D, Bronstein, M, Darvasi, A, Lencz, T, Malhotra, AK, Rujescu, D, Giegling, I, Werge, T, Hansen, T, Ingason, A, Nöethen, MM, Rietschel, M, Cichon, S, Djurovic, S, Andreassen, OA, Cantor, RM, Ophoff, R, Corvin, A, Morris, DW, Gill, M, Pato, CN, Pato, MT, Macedo, A, Gurling, HMD, McQuillin, A, Pimm, J, Hultman, C, Lichtenstein, P, Sklar, P, Purcell, SM, Scolnick, E, Clair, D St, Blackwood, DHR, and Kendler, KS
Published: 2011
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7. Genome-wide association study reveals greater polygenic loading for schizophrenia in cases with a family history of illness

Author: Bigdeli, T. B, Ripke, S, Bacanu, Sa, Lee, S. H, Wray, Nr, Gejman, P. V, Rietschel, M, Cichon, S, St Clair, D, Corvin, A, Kirov, G, Mcquillin, A, Gurling, H, Rujescu, D, Andreassen, O. A, Werge, T, Blackwood, D. H. R, Pato, C. N, Pato, M. T, Malhotra, A. K, O'Donovan, M. C, Kendler, K. S, Fanous, A. H, Neale, Bm, Walters, Jt, Farh, Kh, Holmans, Pa, Lee, P, Bulik Sullivan, B, Collier, Da, Huang, H, Pers, Th, Agartz, I, Agerbo, E, Albus, M, Alexander, M, Amin, F, Begemann, M, Belliveau, Ra, Bene, J, Bergen, Se, Bevilacqua, E, Bigdeli, Tb, Black, Dw, Børglum, Ad, Bruggeman, R, Buccola, Ng, Buckner, Rl, Byerley, W, Cahn, W, Cai, G, Campion, D, Cantor, Rm, Carr, Vj, Carrera, N, Catts, Sv, Chambert, Kd, Chan, Rc, Chen, Ry, Chen, Ey, Cheng, W, Cheung, Ef, Chong, Sa, Cloninger, C, Cohen, D, Cohen, N, Cormican, P, Craddock, N, Crowley, Jj, Curtis, D, Davidson, M, Davis, Kl, Degenhardt, F, Del, Favero, J, Delisi, Le, Demontis, D, Dikeos, D, Dinan, T, Djurovic, S, Donohoe, G, Drapeau, E, Duan, J, Dudbridge, F, Durmishi, N, Eichhammer, P, Eriksson, J, Escott Price, V, Essioux, L, Fanous, Ah, Farrell, Ms, Frank, J, Franke, L, Freedman, R, Freimer, Nb, Friedl, M, Friedman, Ji, Fromer, M, Genovese, G, Georgieva, L, Gershon, Es, Giegling, I, Giusti Rodríguez, P, Godard, S, Goldstein, Ji, Golimbet, V, Gopal, S, Gratten, J, Grove, J, Haan, De, L, Hammer, C, Hamshere, Ml, Hansen, M, Hansen, T, Haroutunian, V, Hartmann, Am, Henskens, Fa, Herms, S, Hirschhorn, Jn, Hoffmann, P, Hofman, A, Hollegaard, Mv, Hougaard, Dm, Ikeda, M, Joa, I, Julìa, A, Kahn, Rs, Kalaydjieva, L, Karachanak Yankova, S, Karjalainen, J, Kavanagh, D, Keller, Mc, Kelly, Bj, Kennedy, Jl, Khrunin, A, Kim, Y, Klovins, J, Knowles, Ja, Konte, B, Kucinskas, V, Kucinskiene, Za, Kuzelova Ptackova, H, Kähler, Ak, Laurent, C, Keong, Jl, Lee, S, Legge, Se, Lerer, B, Li, M, Li, T, Liang, Ky, Lieberman, J, Limborska, S, Loughland, Cm, Lubinski, J, Lönnqvist, J, Macek, M, Magnusson, Pk, Maher, Bs, Maier, W, Mallet, J, Marsal, S, Mattheisen, M, Mattingsdal, M, Mccarley, Rw, Mcdonald, C, Mcintosh, Am, Meier, S, Meijer, Cj, Melegh, B, Melle, I, Mesholam Gately, Ri, Metspalu, A, Michie, Pt, Milani, L, Milanova, V, Mokrab, Y, Morris, Dw, Mors, O, Mortensen, Pb, Murphy, Kc, Murray, Rm, Myin Germeys, I, Müller Myhsok, B, Nelis, M, Nenadic, I, Nertney, Da, Nestadt, G, Nicodemus, Kk, Nikitina Zake, L, Nisenbaum, L, Nordin, A, O'Callaghan, E, O'Dushlaine, C, O'Neill, F, Sy, Oh, Olincy, A, Olsen, L, Jv, Os, Pantelis, C, Papadimitriou, Gn, Papiol, S, Parkhomenko, E, Pato, Mt, Paunio, T, Pejovic Milovancevic, M, Perkins, Do, Pietiläinen, O, Pimm, J, Pocklington, Aj, Powell, J, Price, A, Pulver, Ae, Purcell, Sm, Quested, D, Rasmussen, Hb, Reichenberg, A, Reimers, Ma, Richards, Al, Roffman, Jl, Roussos, P, Ruderfer, Dm, Salomaa, V, Sanders, Ar, Schall, U, Schubert, Cr, Schulze, Tg, Schwab, Sg, Scolnick, Em, Scott, Rj, Seidman, Lj, Shi, J, Sigurdsson, E, Silagadze, T, Silverman, Jm, Sim, K, Slominsky, P, Smoller, Jw, Hc, So, Spencer, Cc, Stahl, Ea, Stefansson, H, Steinberg, S, Stogmann, E, Straub, Re, Strengman, E, Strohmaier, J, Stroup, T, Subramaniam, M, Suvisaari, J, Svrakic, Dm, Szatkiewicz, Jp, Söderman, E, Thirumalai, S, Toncheva, D, Tooney, Pa, Tosato, Sarah, Veijola, J, Waddington, J, Walsh, D, Wang, D, Wang, Q, Webb, Bt, Weiser, M, Wildenauer, Db, Williams, Nm, Williams, S, Witt, Sh, Wolen, Ar, Wong, Eh, Wormley, Bk, Jq, Wu, Hs, Xi, Zai, Cc, Zheng, X, Zimprich, F, Stefansson, K, Visscher, Pm, Adolfsson, R, Andreassen, Oa, Blackwood, Dh, Bramon, E, Buxbaum, Jd, Darvasi, A, Domenici, E, Ehrenreich, H, Esko, T, Gejman, Pv, Gill, M, Hultman, Cm, Iwata, N, Jablensky, Av, Jönsson, Eg, Kendler, Ks, Knight, J, Lencz, T, Levinson, Df, Qs, Li, Liu, J, Malhotra, Ak, Mccarroll, Sa, Moran, Jl, Mowry, Bj, Nöthen, Mm, Ophoff, Ra, Owen, Mj, Palotie, A, Pato, Cn, Petryshen, Tl, Posthuma, D, Riley, Bp, Sham, Pc, Sklar, P, Clair, Ds, Weinberger, Dr, Wendland, Jr, Daly, Mj, Sullivan, Pf, O'Donovan, Mc, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Bigdeli, Tim B, Ripke, Stephan, Bacanu, Silviu-Alin, Lee, Sang Hong, Fanous, Ayman H, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Psychosis Endophenotype International Consortium, Wellcome Trust Case-Control Consortium 2, Other departments, Adult Psychiatry, Psychiatrie & Neuropsychologie, RS: MHeNs - R2 - Mental Health, MUMC+: MA Psychiatrie (3), MUMC+: Hersen en Zenuw Centrum (3), and Del-Favero, Jurgen
Subjects: 0301 basic medicine, Multifactorial Inheritance, Bipolar Disorder, Inheritance Patterns, Genome-wide association study, Single-nucleotide polymorphism, polygenic, heritability, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, medicine, Humans, SNP, GWAS, Family, Genetic Predisposition to Disease, Family history, Allele, Genetics (clinical), Genetic association, Genetics & Heredity, Psychiatry, Genetics, Depressive Disorder, Major, family history, Models, Genetic, Case-control study, medicine.disease, 3. Good health, schizophrenia, Psychiatry and Mental health, 030104 developmental biology, Schizophrenia, Case-Control Studies, Human medicine, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Genome-wide association studies (GWAS) of schizophrenia have yielded more than 100 common susceptibility variants, and strongly support a substantial polygenic contribution of a large number of small allelic effects. It has been hypothesized that familial schizophrenia is largely a consequence of inherited rather than environmental factors. We investigated the extent to which familiality of schizophrenia is associated with enrichment for common risk variants detectable in a large GWAS. We analyzed single nucleotide polymorphism (SNP) data for cases reporting a family history of psychotic illness (N=978), cases reporting no such family history (N=4,503), and unscreened controls (N=8,285) from the Psychiatric Genomics Consortium (PGC1) study of schizophrenia. We used a multinomial logistic regression approach with model-fitting to detect allelic effects specific to either family history subgroup. We also considered a polygenic model, in which we tested whether family history positive subjects carried more schizophrenia risk alleles than family history negative subjects, on average. Several individual SNPs attained suggestive but not genome-wide significant association with either family history subgroup. Comparison of genome-wide polygenic risk scores based on GWAS summary statistics indicated a significant enrichment for SNP effects among family history positive compared to family history negative cases (Nagelkerke's R-2=0.0021; P=0.00331; P-value threshold
Published: 2016
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8. Population-based identity-by-descent mapping combined with exome sequencing to detect rare risk variants for schizophrenia

Author: Harold, D, Connolly, S, Riley, BP, Kendler, KS, McCarthy, SE, McCombie, WR, Richards, A, Owen, MJ, O'Donovan, MC, Walters, J, Donnelly, P, Bates, L, Barroso, I, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, HS, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Viswanathan, AC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Hopkins, L, Pirinen, M, Pearson, R, Strange, A, Su, Z, Vukcevic, D, Langford, C, Hunt, SE, Edkins, S, Gwilliam, R, Blackburn, H, Bumpstead, SJ, Dronov, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, McCann, OT, Liddle, J, Potter, SC, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P, Ripke, S, Neale, BM, Walters, JTR, Farh, K-H, Holmans, PA, Lee, P, Bulik-Sullivan, B, Collier, DA, Huang, H, Pers, TH, Agartz, I, Agerbo, E, Albus, M, Alexander, M-L, Amin, F, Bacanu, SA, Begemann, M, Belliveau, RA, Bene, J, Bergen, SE, Bevilacqua, E, Bigdeli, TB, Black, DW, Bruggeman, R, Buccola, NG, Buckner, RL, Byerley, W, Cahn, W, Cai, G, Campion, D, Cantor, RM, Carr, VJ, Carrera, N, Catts, SV, Chambert, KD, Chan, RCK, Chan, RYL, Chen, EYH, Cheng, W, Cheung, EFC, Chong, SA, Cloninger, CR, Cohen, D, Cohen, N, Cormican, P, Craddock, N, Crowley, JJ, Curtis, D, Davidson, M, Davis, KL, Degenhardt, F, Del Favero, J, Demontis, D, Dikeos, D, Dinan, T, Djurovic, S, Donohoe, G, Drapeau, E, Duan, J, Dudbridge, F, Durmishi, N, Eichhammer, P, Eriksson, J, Escott-Price, V, Essioux, L, Fanous, AH, Farrell, MS, Frank, J, Franke, L, Freedman, R, Freimer, NB, Friedl, M, Friedman, JI, Fromer, M, Genovese, G, Georgieva, L, Giegling, I, Giusti-Rodriguez, P, Godard, S, Goldstein, JI, Golimbet, V, Gopal, S, Gratten, J, de Haan, L, Hammer, C, Hamshere, ML, Hansen, M, Hansen, T, Haroutunian, V, Hartmann, AM, Henskens, FA, Herms, S, Hirschhorn, JN, Hoffmann, P, Hofman, A, Hollegaard, MV, Hougaard, DM, Ikeda, M, Joa, I, Julia, A, Kalaydjieva, L, Karachanak-Yankova, S, Karjalainen, J, Kavanagh, D, Keller, MC, Kennedy, JL, Khrunin, A, Kim, Y, Klovins, J, Knowles, JA, Konte, B, Kucinskas, V, Kucinskiene, ZA, Kuzelova-Ptackova, H, Kahler, AK, Laurent, C, Lee, J, Lee, SH, Legge, SE, Lerer, B, Li, M, Li, T, Liang, K-Y, Lieberman, J, Limborska, S, Loughland, CM, Lubinski, J, Lonnqvist, J, Macek, M, Magnusson, PKE, Maher, BS, Maier, W, Mallet, J, Marsal, S, Mattheisen, M, Mattingsdal, M, McCarley, RW, McDonald, C, McIntosh, AM, Meier, S, Meijer, CJ, Melegh, B, Melle, I, Mesholam-Gately, RI, Metspalu, A, Michie, PT, Milani, L, Milanova, V, Mokrab, Y, Morris, DW, Mors, O, Murphy, KC, Murray, RM, Myin-Germeys, I, Muller-Myhsok, B, Nelis, M, Nenadic, I, Nertney, DA, Nestadt, G, Nicodemus, KK, Nikitina-Zake, L, Nisenbaum, L, Nordin, A, O'Callaghan, E, O'Dushlaine, C, O'Neill, FA, Oh, S-Y, Olincy, A, Olsen, L, Van Os, J, Pantelis, C, Papadimitriou, GN, Papiol, S, Parkhomenko, E, Pato, MT, Paunio, T, Pejovic-Milovancevic, M, Perkins, DO, Pietilainen, O, Pimm, J, Pocklington, AJ, Price, A, Pulver, AE, Purcell, SM, Quested, D, Rasmussen, HB, Reichenberg, A, Reimers, MA, Richards, AL, Roffman, JL, Roussos, P, Ruderfer, DM, Salomaa, V, Sanders, AR, Schall, U, Schubert, CR, Schulze, TG, Schwab, SG, Scolnick, EM, Scott, RJ, Seidman, LJ, Shi, J, Sigurdsson, E, Silagadze, T, Silverman, JM, Sim, K, Slominsky, P, Smoller, JW, So, H-C, Stahl, EA, Stefansson, H, Steinberg, S, Stogmann, E, Straub, RE, Strengman, E, Strohmaier, J, Stroup, TS, Subramaniam, M, Suvisaari, J, Svrakic, DM, Szatkiewicz, JP, Soderman, E, Thirumalai, S, Toncheva, D, Tosato, S, Veijola, J, Waddington, J, Walsh, D, Wang, D, Wang, Q, Webb, BT, Weiser, M, Wildenauer, DB, Williams, NM, Williams, S, Witt, SH, Wolen, AR, Wong, EHM, Wormley, BK, Xi, HS, Zai, CC, Zheng, X, Zimprich, F, Wray, NR, Stefansson, K, Visscher, PM, Adolfsson, R, Andreassen, OA, Blackwood, DHR, Buxbaum, JD, Borglum, AD, Darvasi, A, Domenici, E, Ehrenreich, H, Esko, T, Gejman, PV, Gill, M, Gurling, H, Hultman, CM, Iwata, N, Jablensky, AV, Jonsson, EG, Kirov, G, Knight, J, Lencz, T, Levinson, DF, Li, QS, Liu, J, Malhotra, AK, McCarroll, SA, McQuillin, A, Moran, JL, Mortensen, PB, Mowry, BJ, Palotie, A, Pato, CN, Petryshen, TL, Posthuma, D, Rujescu, D, Sham, PC, Sklar, P, St Clair, D, Weinberger, DR, Wendland, JR, Werge, T, Daly, MJ, Sullivan, PF, Harold, D, Connolly, S, Riley, BP, Kendler, KS, McCarthy, SE, McCombie, WR, Richards, A, Owen, MJ, O'Donovan, MC, Walters, J, Donnelly, P, Bates, L, Barroso, I, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, HS, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Viswanathan, AC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Hopkins, L, Pirinen, M, Pearson, R, Strange, A, Su, Z, Vukcevic, D, Langford, C, Hunt, SE, Edkins, S, Gwilliam, R, Blackburn, H, Bumpstead, SJ, Dronov, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, McCann, OT, Liddle, J, Potter, SC, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P, Ripke, S, Neale, BM, Walters, JTR, Farh, K-H, Holmans, PA, Lee, P, Bulik-Sullivan, B, Collier, DA, Huang, H, Pers, TH, Agartz, I, Agerbo, E, Albus, M, Alexander, M-L, Amin, F, Bacanu, SA, Begemann, M, Belliveau, RA, Bene, J, Bergen, SE, Bevilacqua, E, Bigdeli, TB, Black, DW, Bruggeman, R, Buccola, NG, Buckner, RL, Byerley, W, Cahn, W, Cai, G, Campion, D, Cantor, RM, Carr, VJ, Carrera, N, Catts, SV, Chambert, KD, Chan, RCK, Chan, RYL, Chen, EYH, Cheng, W, Cheung, EFC, Chong, SA, Cloninger, CR, Cohen, D, Cohen, N, Cormican, P, Craddock, N, Crowley, JJ, Curtis, D, Davidson, M, Davis, KL, Degenhardt, F, Del Favero, J, Demontis, D, Dikeos, D, Dinan, T, Djurovic, S, Donohoe, G, Drapeau, E, Duan, J, Dudbridge, F, Durmishi, N, Eichhammer, P, Eriksson, J, Escott-Price, V, Essioux, L, Fanous, AH, Farrell, MS, Frank, J, Franke, L, Freedman, R, Freimer, NB, Friedl, M, Friedman, JI, Fromer, M, Genovese, G, Georgieva, L, Giegling, I, Giusti-Rodriguez, P, Godard, S, Goldstein, JI, Golimbet, V, Gopal, S, Gratten, J, de Haan, L, Hammer, C, Hamshere, ML, Hansen, M, Hansen, T, Haroutunian, V, Hartmann, AM, Henskens, FA, Herms, S, Hirschhorn, JN, Hoffmann, P, Hofman, A, Hollegaard, MV, Hougaard, DM, Ikeda, M, Joa, I, Julia, A, Kalaydjieva, L, Karachanak-Yankova, S, Karjalainen, J, Kavanagh, D, Keller, MC, Kennedy, JL, Khrunin, A, Kim, Y, Klovins, J, Knowles, JA, Konte, B, Kucinskas, V, Kucinskiene, ZA, Kuzelova-Ptackova, H, Kahler, AK, Laurent, C, Lee, J, Lee, SH, Legge, SE, Lerer, B, Li, M, Li, T, Liang, K-Y, Lieberman, J, Limborska, S, Loughland, CM, Lubinski, J, Lonnqvist, J, Macek, M, Magnusson, PKE, Maher, BS, Maier, W, Mallet, J, Marsal, S, Mattheisen, M, Mattingsdal, M, McCarley, RW, McDonald, C, McIntosh, AM, Meier, S, Meijer, CJ, Melegh, B, Melle, I, Mesholam-Gately, RI, Metspalu, A, Michie, PT, Milani, L, Milanova, V, Mokrab, Y, Morris, DW, Mors, O, Murphy, KC, Murray, RM, Myin-Germeys, I, Muller-Myhsok, B, Nelis, M, Nenadic, I, Nertney, DA, Nestadt, G, Nicodemus, KK, Nikitina-Zake, L, Nisenbaum, L, Nordin, A, O'Callaghan, E, O'Dushlaine, C, O'Neill, FA, Oh, S-Y, Olincy, A, Olsen, L, Van Os, J, Pantelis, C, Papadimitriou, GN, Papiol, S, Parkhomenko, E, Pato, MT, Paunio, T, Pejovic-Milovancevic, M, Perkins, DO, Pietilainen, O, Pimm, J, Pocklington, AJ, Price, A, Pulver, AE, Purcell, SM, Quested, D, Rasmussen, HB, Reichenberg, A, Reimers, MA, Richards, AL, Roffman, JL, Roussos, P, Ruderfer, DM, Salomaa, V, Sanders, AR, Schall, U, Schubert, CR, Schulze, TG, Schwab, SG, Scolnick, EM, Scott, RJ, Seidman, LJ, Shi, J, Sigurdsson, E, Silagadze, T, Silverman, JM, Sim, K, Slominsky, P, Smoller, JW, So, H-C, Stahl, EA, Stefansson, H, Steinberg, S, Stogmann, E, Straub, RE, Strengman, E, Strohmaier, J, Stroup, TS, Subramaniam, M, Suvisaari, J, Svrakic, DM, Szatkiewicz, JP, Soderman, E, Thirumalai, S, Toncheva, D, Tosato, S, Veijola, J, Waddington, J, Walsh, D, Wang, D, Wang, Q, Webb, BT, Weiser, M, Wildenauer, DB, Williams, NM, Williams, S, Witt, SH, Wolen, AR, Wong, EHM, Wormley, BK, Xi, HS, Zai, CC, Zheng, X, Zimprich, F, Wray, NR, Stefansson, K, Visscher, PM, Adolfsson, R, Andreassen, OA, Blackwood, DHR, Buxbaum, JD, Borglum, AD, Darvasi, A, Domenici, E, Ehrenreich, H, Esko, T, Gejman, PV, Gill, M, Gurling, H, Hultman, CM, Iwata, N, Jablensky, AV, Jonsson, EG, Kirov, G, Knight, J, Lencz, T, Levinson, DF, Li, QS, Liu, J, Malhotra, AK, McCarroll, SA, McQuillin, A, Moran, JL, Mortensen, PB, Mowry, BJ, Palotie, A, Pato, CN, Petryshen, TL, Posthuma, D, Rujescu, D, Sham, PC, Sklar, P, St Clair, D, Weinberger, DR, Wendland, JR, Werge, T, Daly, MJ, and Sullivan, PF
Abstract: Genome-wide association studies (GWASs) are highly effective at identifying common risk variants for schizophrenia. Rare risk variants are also important contributors to schizophrenia etiology but, with the exception of large copy number variants, are difficult to detect with GWAS. Exome and genome sequencing, which have accelerated the study of rare variants, are expensive so alternative methods are needed to aid detection of rare variants. Here we re-analyze an Irish schizophrenia GWAS dataset (n = 3,473) by performing identity-by-descent (IBD) mapping followed by exome sequencing of individuals identified as sharing risk haplotypes to search for rare risk variants in coding regions. We identified 45 rare haplotypes (>1 cM) that were significantly more common in cases than controls. By exome sequencing 105 haplotype carriers, we investigated these haplotypes for functional coding variants that could be tested for association in independent GWAS samples. We identified one rare missense variant in PCNT but did not find statistical support for an association with schizophrenia in a replication analysis. However, IBD mapping can prioritize both individual samples and genomic regions for follow-up analysis but genome rather than exome sequencing may be more effective at detecting risk variants on rare haplotypes.
Published: 2019

9. Genome-wide association study identifies genetic loci for self-reported habitual sleep duration supported by accelerometer-derived estimates

Author: Dashti, HS, Jones, SE, Wood, AR, Lane, JM, van Hees, VT, Wang, HM, Rhodes, JA, Song, YW, Patel, KN, Anderson, SG, Beaumont, RN, Bechtold, DA, Bowden, J, Cade, BE, Garaulet, M, Kyle, SD, Little, M A, Loudon, AS, Luik, AI, Scheer, F, Spiegelhalder, K, Tyrrell, J, Gottlieb, DJ, Tiemeier, Henning, Ray, DW, Purcell, SM, Frayling, TM, Redline, S, Lawlor, DA, Rutter, MK, Weedon, MN, Saxena, R, Dashti, HS, Jones, SE, Wood, AR, Lane, JM, van Hees, VT, Wang, HM, Rhodes, JA, Song, YW, Patel, KN, Anderson, SG, Beaumont, RN, Bechtold, DA, Bowden, J, Cade, BE, Garaulet, M, Kyle, SD, Little, M A, Loudon, AS, Luik, AI, Scheer, F, Spiegelhalder, K, Tyrrell, J, Gottlieb, DJ, Tiemeier, Henning, Ray, DW, Purcell, SM, Frayling, TM, Redline, S, Lawlor, DA, Rutter, MK, Weedon, MN, and Saxena, R
Published: 2019

10. Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases

Author: Gusev, A, Lee, Sh, SWE SCZ, Consortium, O'Dushlaine, Cgusev, Trynka, G, Finucane, H, Vilhjálmsson, Bj, Xu, H, Zang, C, Ripke, S, Bulik Sullivan, B, Stahl, E, Schizophrenia, Working, Neale, Bm, Corvin, A, Walters, Jt, Farh, Kh, Holmans, Pa, Lee, P, Collier, Da, Huang, H, Pers, Th, Agartz, I, Agerbo, E, Albus, M, Alexander, M, Amin, F, Bacanu, Sa, Begemann, M, Belliveau, Ra, Bene, J, Bergen, Se, Bevilacqua, E, Bigdeli, Tb, Black, Dw, Børglum, Ad, Bruggeman, R, Buccola, Ng, Buckner, Rl, Byerley, W, Cahn, W, Cai, G, Campion, D, Cantor, Rm, Carr, Vj, Carrera, N, Catts, Sv, Chambert, Kd, Chan, Rc, Chen, Ry, Chen, Ey, Cheng, W, Cheung, Ef, Chong, Sa, Cloninger, Cr, Cohen, D, Cohen, N, Cormican, P, Craddock, N, Crowley, Jj, Curtis, D, Davidson, M, Davis, Kl, Degenhardt, F, Del, Favero, Delisi, Le, Demontis, D, Dikeos, D, Dinan, T, Djurovic, S, Donohoe, G, Drapeau, E, Duan, J, Dudbridge, F, Durmishi, N, Eichhammer, P, Eriksson, J, Escott Price, V, Essioux, L, Fanous, Ah, Farrell, Ms, Frank, J, Franke, L, Freedman, R, Freimer, Nb, Friedl, M, Friedman, Ji, Fromer, M, Genovese, G, Georgieva, L, Gershon, Es, Giegling, I, Giusti Rodrguez, P, Godard, S, Goldstein, Ji, Golimbet, V, Gopal, S, Gratten, J, Grove, J, Haan, De, Hammer, C, Hamshere, Ml, Hansen, M, Hansen, T, Haroutunian, V, Hartmann, Am, Henskens, Fa, Herms, S, Hirschhorn, Jn, Hoffmann, P, Hofman, A, Hollegaard, Mv, Hougaard, Dm, Ikeda, M, Joa, I, Julià, A, Kahn, Rs, Kalaydjieva, L, Karachanak Yankova, S, Karjalainen, J, Kavanagh, D, Keller, Mc, Kelly, Bj, Kennedy, Jl, Khrunin, A, Kim, Y, Klovins, J, Knowles, Ja, Konte, B, Kucinskas, V, Kucinskiene, Za, Kuzelova Ptackova, H, Kähler, Ak, Laurent, C, Keong, Jl, Legge, Se, Lerer, B, Li, M, Li, T, Liang, Ky, Lieberman, J, Limborska, S, Loughland, Cm, Lubinski, J, Lnnqvist, J, Macek, M, Magnusson, Pk, Maher, Bs, Maier, W, Mallet, J, Marsal, S, Mattheisen, M, Mattingsdal, M, Mccarley, Rw, Mcdonald, C, Mcintosh, Am, Meier, S, Meijer, Cj, Melegh, B, Melle, I, Mesholam Gately, Ri, Metspalu, A, Michie, Pt, Milani, L, Milanova, V, Mokrab, Y, Morris, Dw, Mors, O, Mortensen, Pb, Murphy, Kc, Murray, Rm, Myin Germeys, I, Mller Myhsok, B, Nelis, M, Nenadic, I, Nertney, Da, Nestadt, G, Nicodemus, Kk, Nikitina Zake, L, Nisenbaum, L, Nordin, A, O'Callaghan, E, O'Dushlaine, C, O'Neill, Fa, Sy, Oh, Olincy, A, Olsen, L, Van, Os, Pantelis, C, Papadimitriou, Gn, Papiol, S, Parkhomenko, E, Pato, Mt, Paunio, T, Pejovic Milovancevic, M, Perkins, Do, Pietilinen, O, Pimm, J, Pocklington, Aj, Powell, J, Price, A, Pulver, Ae, Purcell, Sm, Quested, D, Rasmussen, Hb, Reichenberg, A, Reimers, Ma, Richards, Al, Roffman, Jl, Roussos, P, Ruderfer, Dm, Salomaa, V, Sanders, Ar, Schall, U, Schubert, Cr, Schulze, Tg, Schwab, Sg, Scolnick, Em, Scott, Rj, Seidman, Lj, Shi, J, Sigurdsson, E, Silagadze, T, Silverman, Jm, Sim, K, Slominsky, P, Smoller, Jw, Hc, So, Spencer, Cc, Stahl, Ea, Stefansson, H, Steinberg, S, Stogmann, E, Straub, Re, Strengman, E, Strohmaier, J, Stroup, Ts, Subramaniam, M, Suvisaari, J, Svrakic, Dm, Szatkiewicz, Jp, Sderman, E, Thirumalai, S, Toncheva, D, Tooney, Pa, Tosato, Sarah, Veijola, J, Waddington, J, Walsh, D, Wang, D, Wang, Q, Webb, Bt, Weiser, M, Wildenauer, Db, Williams, Nm, Williams, S, Witt, Sh, Wolen, Ar, Wong, Eh, Wormley, Bk, Jq, Wu, Hs, Xi, Zai, Cc, Zheng, X, Zimprich, F, Wray, Nr, Stefansson, K, Visscher, Pm, Adolfsson, R, Andreassen, Oa, Blackwood, Dh, Bramon, E, Buxbaum, Jd, Brglum, Ad, Cichon, S, Darvasi, A, Domenici, E, Ehrenreich, H, Esko, T, Gejman, Pv, Gill, M, Gurling, H, Hultman, Cm, Iwata, N, Jablensky, Av, Jönsson, Eg, Kendler, Ks, Kirov, G, Knight, J, Lencz, T, Levinson, Df, Qs, Li, Liu, J, Malhotra, Ak, Mccarroll, Sa, Mcquillin, A, Moran, Jl, Mowry, Bj, Nthen, Mm, Ophoff, Ra, Owen, Mj, Palotie, A, Pato, Cn, Petryshen, Tl, Posthuma, D, Rietschel, M, Riley, Bp, Rujescu, D, Sham, Pc, Sklar, P, Clair, St, Weinberger, Dr, Wendland, Jr, Werge, T, Daly, Mj, Sullivan, Pf, O'Donovan, Mc, Chambert, K, Akterin, S, Bergen, S, Ruderfer, D, Scolnick, E, Purcell, S, Mccarroll, S, Daly, M, Pasaniuc, B, Raychaudhuri, S, Price, Al, Gusev, Alexander, Lee, S Hong, Trynka, Gosia, Finucane, Hilary K, Price, Alkes L, Schizophrenia Working Group of the Psychiatric Genomics Consortium, SWE-SCZ Consortium, ANS - Amsterdam Neuroscience, Adult Psychiatry, Other departments, Psychiatrie & Neuropsychologie, RS: MHeNs - R2 - Mental Health, Complex Trait Genetics, Functional Genomics, and Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease
Subjects: Linkage disequilibrium, GWAS, schizophrenia, SNP, trait heritability, disease architecture, Inheritance Patterns, Single-nucleotide polymorphism, Genome-wide association study, Biology, Article, Open Reading Frames, SDG 3 - Good Health and Well-being, Genetic, Models, Genotype, Genetics, Humans, Genetics(clinical), Computer Simulation, Regulatory Elements, Transcriptional, Exome, Genetics (clinical), genotype imputation, Genetic association, Genetics & Heredity, genome-wide association study, Models, Genetic, Genetic Diseases, Inborn, Genetic Variation, Heritability, exome chips, Regulatory Elements, Inborn, Genetic Diseases, Transcriptional, coding variants, Genome-Wide Association Study
Abstract: Regulatory and coding variants are known to be enriched with associations identified by genome-wide association studies (GWASs) of complex disease, but their contributions to trait heritability are currently unknown. We applied variance-component methods to imputed genotype data for 11 common diseases to partition the heritability explained by genotyped SNPs (h(g)(2)) across functional categories (while accounting for shared variance due to linkage disequilibrium). Extensive simulations showed that in contrast to current estimates from GWAS summary statistics, the variance-component approach partitions heritability accurately under a wide range of complex-disease architectures. Across the 11 diseases DNaseI hypersensitivity sites (DHSs) from 217 cell types spanned 16% of imputed SNPs (and 24% of genotyped SNPs) but explained an average of 79% (SE = 8%) of h(g)(2) from imputed SNPs (5.1 x enrichment; p = 3.7 x 10(-17)) and 38% (SE = 4%) of h(g)(2) from genotyped SNPs (1.6 x enrichment, p = 1.0 x 10(-4)). Further enrichment was observed at enhancer DHSs and cell-type-specific DHSs. In contrast, coding variants, which span 1% of the genome, explained
Published: 2014
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11. Age at first birth in women is genetically associated with increased risk of schizophrenia

Author: Ni, G, Gratten, J, Wray, NR, Lee, SH, Ripke, S, Neale, BM, Corvin, A, Walters, JTR, Farh, KH, Holmans, PA, Lee, P, Bulik-Sullivan, B, Collier, DA, Huang, H, Pers, TH, Agartz, I, Agerbo, E, Albus, M, Alexander, M, Amin, F, Bacanu, SA, Begemann, M, Belliveau, RA, Bene, J, Bergen, SE, Bevilacqua, E, Bigdeli, TB, Black, DW, Bruggeman, R, Buccola, NG, Buckner, RL, Byerley, W, Cahn, W, Cai, G, Campion, D, Cantor, RM, Carr, VJ, Carrera, N, Catts, SV, Chambert, KD, Chan, RCK, Chen, RYL, Chen, EYH, Cheng, W, Cheung, EFC, Chong, SA, Cloninger, CR, Cohen, D, Cohen, N, Cormican, P, Craddock, N, Crowley, JJ, Curtis, D, Davidson, M, Davis, KL, Degenhardt, F, Del Favero, J, Demontis, D, Dikeos, D, Dinan, T, Djurovic, S, Donohoe, G, Drapeau, E, Duan, J, Dudbridge, F, Durmishi, N, Eichhammer, P, Eriksson, J, Escott-Price, V, Essioux, L, Fanous, AH, Farrell, MS, Frank, J, Franke, L, Freedman, R, Freimer, NB, Friedl, M, Friedman, JI, Fromer, M, Genovese, G, Georgieva, L, Giegling, I, Giusti-Rodríguez, P, Godard, S, Goldstein, JI, Golimbet, V, Gopal, S, Haan, L de, Hammer, C, Hamshere, ML, Hansen, M, Hansen, T, Haroutunian, V, Hartmann, AM, Henskens, FA, Herms, S, Hirschhorn, JN, Hoffmann, P, Hofman, A, Hollegaard, MV, Hougaard, DM, Ikeda, M, Joa, I, Juliá, A, Kahn, RS, Kalaydjieva, L, Karachanak-Yankova, S, Karjalainen, J, Kavanagh, D, Keller, MC, Kennedy, JL, Khrunin, A, Kim, Y, Klovins, J, Knowles, JA, Konte, B, Kucinskas, V, Kucinskiene, ZA, Kuzelova-Ptackova, H, Kähler, AK, Laurent, C, Keong, JLC, Legge, SE, Lerer, B, Li, M, Li, T, Liang, KY, Lieberman, J, Limborska, S, Loughland, CM, Lubinski, J, Lönnqvist, J, Macek, M, Magnusson, PKE, Maher, BS, Maier, W, Mallet, J, Marsal, S, Mattheisen, M, Mattingsdal, M, McCarley, RW, McDonald, C, McIntosh, AM, Meier, S, Meijer, CJ, Melegh, B, Melle, I, Mesholam-Gately, RI, Metspalu, A, Michie, PT, Milani, L, Milanova, V, Mokrab, Y, Morris, DW, Mors, O, Murphy, KC, Murray, RM, Myin-Germeys, I, Müller-Myhsok, B, Nelis, M, Nenadic, I, Nertney, DA, Nestadt, G, Nicodemus, KK, Nikitina-Zake, L, Nisenbaum, L, Nordin, A, O'Callaghan, E, O'Dushlaine, C, O'Neill, FA, Oh, SY, Olincy, A, Olsen, L, van Os, JV, Pantelis, C, Papadimitriou, GN, Papiol, S, Parkhomenko, E, Pato, MT, Paunio, T, Pejovic-Milovancevic, M, Perkins, DO, Pietiläinen, O, Pimm, J, Pocklington, AJ, Powell, J, Price, A, Pulver, AE, Purcell, SM, Quested, D, Rasmussen, HB, Reichenberg, A, Reimers, MA, Richards, AL, Roffman, JL, Roussos, P, Ruderfer, DM, Salomaa, V, Sanders, AR, Schall, U, Schubert, CR, Schulze, TG, Schwab, SG, Scolnick, EM, Scott, RJ, Seidman, LJ, Shi, J, Sigurdsson, E, Silagadze, T, Silverman, JM, Sim, K, Slominsky, P, Smoller, JW, So, HC, Spencer, CCA, Stahl, EA, Stefansson, H, Steinberg, S, Stogmann, E, Straub, RE, Strengman, E, Strohmaier, J, Stroup, TS, Subramaniam, M, Suvisaari, J, Svrakic, DM, Szatkiewicz, JP, Söderman, E, Thirumalai, S, Toncheva, D, Tosato, S, Veijola, J, Waddington, J, Walsh, D, Wang, D, Wang, Q, Webb, BT, Weiser, M, Wildenauer, DB, Williams, NM, Williams, S, Witt, SH, Wolen, AR, Wong, EHM, Wormley, BK, Xi, HS, Zai, CC, Zheng, Xuebin, Zimprich, F, Stefansson, K, Visscher, PM, Adolfsson, R, Andreassen, OA, Blackwood, DHR, Bramon, E, Buxbaum, JD, Børglum, AD, Cichon, S, Darvasi, A, Domenici, E, Ehrenreich, H, Esko, T, Gejman, PV, Gill, M, Gurling, H, Hultman, CM, Iwata, N, Jablensky, AV, Jönsson, EG, Kendler, KS, Kirov, G, Knight, J, Lencz, T, Levinson, DF, Li, QS, Liu, J, Malhotra, AK, McCarroll, SA, McQuillin, A, Moran, JL, Mortensen, PB, Mowry, BJ, Nöthen, MM, Ophoff, RA, Owen, MJ, Palotie, A, Pato, CN, Petryshen, TL, Posthuma, Daniëlle, Rietschel, M, Riley, BP, Rujescu, D, Sham, PC, Clair, DS, Weinberger, DR, Wendland, JR, Werge, T, Daly, MJ, Sullivan, PF, O'Donovan, MC, Ni, G, Gratten, J, Wray, NR, Lee, SH, Ripke, S, Neale, BM, Corvin, A, Walters, JTR, Farh, KH, Holmans, PA, Lee, P, Bulik-Sullivan, B, Collier, DA, Huang, H, Pers, TH, Agartz, I, Agerbo, E, Albus, M, Alexander, M, Amin, F, Bacanu, SA, Begemann, M, Belliveau, RA, Bene, J, Bergen, SE, Bevilacqua, E, Bigdeli, TB, Black, DW, Bruggeman, R, Buccola, NG, Buckner, RL, Byerley, W, Cahn, W, Cai, G, Campion, D, Cantor, RM, Carr, VJ, Carrera, N, Catts, SV, Chambert, KD, Chan, RCK, Chen, RYL, Chen, EYH, Cheng, W, Cheung, EFC, Chong, SA, Cloninger, CR, Cohen, D, Cohen, N, Cormican, P, Craddock, N, Crowley, JJ, Curtis, D, Davidson, M, Davis, KL, Degenhardt, F, Del Favero, J, Demontis, D, Dikeos, D, Dinan, T, Djurovic, S, Donohoe, G, Drapeau, E, Duan, J, Dudbridge, F, Durmishi, N, Eichhammer, P, Eriksson, J, Escott-Price, V, Essioux, L, Fanous, AH, Farrell, MS, Frank, J, Franke, L, Freedman, R, Freimer, NB, Friedl, M, Friedman, JI, Fromer, M, Genovese, G, Georgieva, L, Giegling, I, Giusti-Rodríguez, P, Godard, S, Goldstein, JI, Golimbet, V, Gopal, S, Haan, L de, Hammer, C, Hamshere, ML, Hansen, M, Hansen, T, Haroutunian, V, Hartmann, AM, Henskens, FA, Herms, S, Hirschhorn, JN, Hoffmann, P, Hofman, A, Hollegaard, MV, Hougaard, DM, Ikeda, M, Joa, I, Juliá, A, Kahn, RS, Kalaydjieva, L, Karachanak-Yankova, S, Karjalainen, J, Kavanagh, D, Keller, MC, Kennedy, JL, Khrunin, A, Kim, Y, Klovins, J, Knowles, JA, Konte, B, Kucinskas, V, Kucinskiene, ZA, Kuzelova-Ptackova, H, Kähler, AK, Laurent, C, Keong, JLC, Legge, SE, Lerer, B, Li, M, Li, T, Liang, KY, Lieberman, J, Limborska, S, Loughland, CM, Lubinski, J, Lönnqvist, J, Macek, M, Magnusson, PKE, Maher, BS, Maier, W, Mallet, J, Marsal, S, Mattheisen, M, Mattingsdal, M, McCarley, RW, McDonald, C, McIntosh, AM, Meier, S, Meijer, CJ, Melegh, B, Melle, I, Mesholam-Gately, RI, Metspalu, A, Michie, PT, Milani, L, Milanova, V, Mokrab, Y, Morris, DW, Mors, O, Murphy, KC, Murray, RM, Myin-Germeys, I, Müller-Myhsok, B, Nelis, M, Nenadic, I, Nertney, DA, Nestadt, G, Nicodemus, KK, Nikitina-Zake, L, Nisenbaum, L, Nordin, A, O'Callaghan, E, O'Dushlaine, C, O'Neill, FA, Oh, SY, Olincy, A, Olsen, L, van Os, JV, Pantelis, C, Papadimitriou, GN, Papiol, S, Parkhomenko, E, Pato, MT, Paunio, T, Pejovic-Milovancevic, M, Perkins, DO, Pietiläinen, O, Pimm, J, Pocklington, AJ, Powell, J, Price, A, Pulver, AE, Purcell, SM, Quested, D, Rasmussen, HB, Reichenberg, A, Reimers, MA, Richards, AL, Roffman, JL, Roussos, P, Ruderfer, DM, Salomaa, V, Sanders, AR, Schall, U, Schubert, CR, Schulze, TG, Schwab, SG, Scolnick, EM, Scott, RJ, Seidman, LJ, Shi, J, Sigurdsson, E, Silagadze, T, Silverman, JM, Sim, K, Slominsky, P, Smoller, JW, So, HC, Spencer, CCA, Stahl, EA, Stefansson, H, Steinberg, S, Stogmann, E, Straub, RE, Strengman, E, Strohmaier, J, Stroup, TS, Subramaniam, M, Suvisaari, J, Svrakic, DM, Szatkiewicz, JP, Söderman, E, Thirumalai, S, Toncheva, D, Tosato, S, Veijola, J, Waddington, J, Walsh, D, Wang, D, Wang, Q, Webb, BT, Weiser, M, Wildenauer, DB, Williams, NM, Williams, S, Witt, SH, Wolen, AR, Wong, EHM, Wormley, BK, Xi, HS, Zai, CC, Zheng, Xuebin, Zimprich, F, Stefansson, K, Visscher, PM, Adolfsson, R, Andreassen, OA, Blackwood, DHR, Bramon, E, Buxbaum, JD, Børglum, AD, Cichon, S, Darvasi, A, Domenici, E, Ehrenreich, H, Esko, T, Gejman, PV, Gill, M, Gurling, H, Hultman, CM, Iwata, N, Jablensky, AV, Jönsson, EG, Kendler, KS, Kirov, G, Knight, J, Lencz, T, Levinson, DF, Li, QS, Liu, J, Malhotra, AK, McCarroll, SA, McQuillin, A, Moran, JL, Mortensen, PB, Mowry, BJ, Nöthen, MM, Ophoff, RA, Owen, MJ, Palotie, A, Pato, CN, Petryshen, TL, Posthuma, Daniëlle, Rietschel, M, Riley, BP, Rujescu, D, Sham, PC, Clair, DS, Weinberger, DR, Wendland, JR, Werge, T, Daly, MJ, Sullivan, PF, and O'Donovan, MC
Published: 2018

12. 0001 GENOME-WIDE ANALYSES OF SLEEP SPINDLES IN THE NATIONAL SLEEP RESEARCH RESOURCE

Author: Panagiotaropoulou, G, primary, Cade, B, additional, Mariani, S, additional, Demanuale, C, additional, Cox, R, additional, Saxena, R, additional, Pan, J, additional, Smoller, J, additional, Stickgold, R, additional, Manoach, D, additional, Redline, S, additional, and Purcell, SM, additional
Published: 2017
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13. Arc Requires PSD95 for Assembly into Postsynaptic Complexes Involved with Neural Dysfunction and Intelligence

Author: Fernandez, E, Collins, MO, Frank, RAW, Zhu, F, Kopanitsa, MV, Nithianantharajah, J, Lempriere, SA, Fricker, D, Elsegood, KA, McLaughlin, CL, Croning, MDR, Mclean, C, Armstrong, JD, Hill, WD, Deary, IJ, Cencelli, G, Bagni, C, Fromer, M, Purcell, SM, Pocklington, AJ, Choudhary, JS, Komiyama, NH, Grant, SGN, Fernandez, E, Collins, MO, Frank, RAW, Zhu, F, Kopanitsa, MV, Nithianantharajah, J, Lempriere, SA, Fricker, D, Elsegood, KA, McLaughlin, CL, Croning, MDR, Mclean, C, Armstrong, JD, Hill, WD, Deary, IJ, Cencelli, G, Bagni, C, Fromer, M, Purcell, SM, Pocklington, AJ, Choudhary, JS, Komiyama, NH, and Grant, SGN
Abstract: Arc is an activity-regulated neuronal protein, but little is known about its interactions, assembly into multiprotein complexes, and role in human disease and cognition. We applied an integrated proteomic and genetic strategy by targeting a tandem affinity purification (TAP) tag and Venus fluorescent protein into the endogenous Arc gene in mice. This allowed biochemical and proteomic characterization of native complexes in wild-type and knockout mice. We identified many Arc-interacting proteins, of which PSD95 was the most abundant. PSD95 was essential for Arc assembly into 1.5-MDa complexes and activity-dependent recruitment to excitatory synapses. Integrating human genetic data with proteomic data showed that Arc-PSD95 complexes are enriched in schizophrenia, intellectual disability, autism, and epilepsy mutations and normal variants in intelligence. We propose that Arc-PSD95 postsynaptic complexes potentially affect human cognitive function.
Published: 2017

14. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways

Author: O’dushlaine, C, Rossin, L, Lee, PH, Duncan, L, Parikshak, NN, Newhouse, S, Ripke, S, Neale, BM, Purcell, SM, Posthuma, D, Nurnberger, JI, Lee, SH, Faraone, SV, Perlis, RH, Mowry, BJ, Thapar, A, Goddard, ME, Witte, JS, Absher, D, Agartz, I, Akil, H, Amin, F, Andreassen, OA, Anjorin, A, Anney, R, Anttila, V, Arking, DE, Asherson, P, Azevedo, MH, Backlund, L, Badner, JA, Bailey, AJ, Banaschewski, T, Barchas, JD, Barnes, MR, Barrett, TB, Bass, N, Battaglia, A, Bauer, M, Bayés, M, Bellivier, F, Bergen, SE, Berrettini, W, Betancur, C, Bettecken, T, Biederman, J, Binder, EB, Black, DW, Blackwood, DHR, Bloss, CS, Boehnke, M, Boomsma, DI, Breuer, R, Bruggeman, R, Cormican, P, Buccola, NG, Buitelaar, JK, Bunney, WE, Buxbaum, JD, Byerley, WF, Byrne, EM, Caesar, S, Cahn, W, Cantor, RM, Casas, M, Chakravarti, A, Chambert, K, Choudhury, K, and Cichon, S
Abstract: © 2015 Nature America, Inc. All rights reserved. Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders.
Published: 2015
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15. Biological insights from 108 schizophrenia-associated genetic loci

Author: Ripke, S, Neale, BM, Corvin, A, Walters, JTR, Farh, K-H, Holmans, PA, Lee, P, Bulik-Sullivan, B, Collier, DA, Huang, H, Pers, TH, Agartz, I, Agerbo, E, Albus, M, Alexander, M, Amin, F, Bacanu, SA, Begemann, M, Belliveau, RA, Bene, J, Bergen, SE, Bevilacqua, E, Bigdeli, TB, Black, DW, Bruggeman, R, Buccola, NG, Buckner, RL, Byerley, W, Cahn, W, Cai, G, Campion, D, Cantor, RM, Carr, VJ, Carrera, N, Catts, SV, Chambert, KD, Chan, RCK, Chen, RYL, Chen, EYH, Cheng, W, Cheung, EFC, Chong, SA, Cloninger, CR, Cohen, D, Cohen, N, Cormican, P, Craddock, N, Crowley, JJ, Curtis, D, Davidson, M, Davis, KL, Degenhardt, F, Del Favero, J, Demontis, D, Dikeos, D, Dinan, T, Djurovic, S, Donohoe, G, Drapeau, E, Duan, J, Dudbridge, F, Durmishi, N, Eichhammer, P, Eriksson, J, Escott-Price, V, Essioux, L, Fanous, AH, Farrell, MS, Frank, J, Franke, L, Freedman, R, Freimer, NB, Friedl, M, Friedman, JI, Fromer, M, Genovese, G, Georgieva, L, Giegling, I, Giusti-Rodriguez, P, Godard, S, Goldstein, JI, Golimbet, V, Gopal, S, Gratten, J, de Haan, L, Hammer, C, Hamshere, ML, Hansen, M, Hansen, T, Haroutunian, V, Hartmann, AM, Henskens, FA, Herms, S, Hirschhorn, JN, Hoffmann, P, Hofman, A, Hollegaard, MV, Hougaard, DM, Ikeda, M, Joa, I, Julia, A, Kahn, RS, Kalaydjieva, L, Karachanak-Yankova, S, Karjalainen, J, Kavanagh, D, Keller, MC, Kennedy, JL, Khrunin, A, Kim, Y, Klovins, J, Knowles, JA, Konte, B, Kucinskas, V, Kucinskiene, ZA, Kuzelova-Ptackova, H, Kahler, AK, Laurent, C, Keong, JLC, Lee, SH, Legge, SE, Lerer, B, Li, M, Li, T, Liang, K-Y, Lieberman, J, Limborska, S, Loughland, CM, Lubinski, J, Lonnqvist, J, Macek, M, Magnusson, PKE, Maher, BS, Maier, W, Mallet, J, Marsal, S, Mattheisen, M, Mattingsdal, M, McCarley, RW, McDonald, C, McIntosh, AM, Meier, S, Meijer, CJ, Melegh, B, Melle, I, Mesholam-Gately, RI, Metspalu, A, Michie, PT, Milani, L, Milanova, V, Mokrab, Y, Morris, DW, Mors, O, Murphy, KC, Murray, RM, Myin-Germeys, I, Mueller-Myhsok, B, Nelis, M, Nenadic, I, Nertney, DA, Nestadt, G, Nicodemus, KK, Nikitina-Zake, L, Nisenbaum, L, Nordin, A, O'Callaghan, E, O'Dushlaine, C, O'Neill, FA, Oh, S-Y, Olincy, A, Olsen, L, Van Os, J, Pantelis, C, Papadimitriou, GN, Papiol, S, Parkhomenko, E, Pato, MT, Paunio, T, Pejovic-Milovancevic, M, Perkins, DO, Pietilainen, O, Pimm, J, Pocklington, AJ, Powell, J, Price, A, Pulver, AE, Purcell, SM, Quested, D, Rasmussen, HB, Reichenberg, A, Reimers, MA, Richards, AL, Roffman, JL, Roussos, P, Ruderfer, DM, Salomaa, V, Sanders, AR, Schall, U, Schubert, CR, Schulze, TG, Schwab, SG, Scolnick, EM, Scott, RJ, Seidman, LJ, Shi, J, Sigurdsson, E, Silagadze, T, Silverman, JM, Sim, K, Slominsky, P, Smoller, JW, So, H-C, Spencer, CCA, Stahl, EA, Stefansson, H, Steinberg, S, Stogmann, E, Straub, RE, Strengman, E, Strohmaier, J, Stroup, TS, Subramaniam, M, Suvisaari, J, Svrakic, DM, Szatkiewicz, JP, Soderman, E, Thirumalai, S, Toncheva, D, Tosato, S, Veijola, J, Waddington, J, Walsh, D, Wang, D, Wang, Q, Webb, BT, Weiser, M, Wildenauer, DB, Williams, NM, Williams, S, Witt, SH, Wolen, AR, Wong, EHM, Wormley, BK, Xi, HS, Zai, CC, Zheng, X, Zimprich, F, Wray, NR, Stefansson, K, Visscher, PM, Adolfsson, R, Andreassen, OA, Blackwood, DHR, Bramon, E, Buxbaum, JD, Borglum, AD, Cichon, S, Darvasi, A, Domenici, E, Ehrenreich, H, Esko, T, Gejman, PV, Gill, M, Gurling, H, Hultman, CM, Iwata, N, Jablensky, AV, Jonsson, EG, Kendler, KS, Kirov, G, Knight, J, Lencz, T, Levinson, DF, Li, QS, Liu, J, Malhotra, AK, McCarroll, SA, McQuillin, A, Moran, JL, Mortensen, PB, Mowry, BJ, Noethen, MM, Ophoff, RA, Owen, MJ, Palotie, A, Pato, CN, Petryshen, TL, Posthuma, D, Rietschel, M, Riley, BP, Rujescu, D, Sham, PC, Sklar, P, St Clair, D, Weinberger, DR, Wendland, JR, Werge, T, Daly, MJ, Sullivan, PF, O'Donovan, MC, Ripke, S, Neale, BM, Corvin, A, Walters, JTR, Farh, K-H, Holmans, PA, Lee, P, Bulik-Sullivan, B, Collier, DA, Huang, H, Pers, TH, Agartz, I, Agerbo, E, Albus, M, Alexander, M, Amin, F, Bacanu, SA, Begemann, M, Belliveau, RA, Bene, J, Bergen, SE, Bevilacqua, E, Bigdeli, TB, Black, DW, Bruggeman, R, Buccola, NG, Buckner, RL, Byerley, W, Cahn, W, Cai, G, Campion, D, Cantor, RM, Carr, VJ, Carrera, N, Catts, SV, Chambert, KD, Chan, RCK, Chen, RYL, Chen, EYH, Cheng, W, Cheung, EFC, Chong, SA, Cloninger, CR, Cohen, D, Cohen, N, Cormican, P, Craddock, N, Crowley, JJ, Curtis, D, Davidson, M, Davis, KL, Degenhardt, F, Del Favero, J, Demontis, D, Dikeos, D, Dinan, T, Djurovic, S, Donohoe, G, Drapeau, E, Duan, J, Dudbridge, F, Durmishi, N, Eichhammer, P, Eriksson, J, Escott-Price, V, Essioux, L, Fanous, AH, Farrell, MS, Frank, J, Franke, L, Freedman, R, Freimer, NB, Friedl, M, Friedman, JI, Fromer, M, Genovese, G, Georgieva, L, Giegling, I, Giusti-Rodriguez, P, Godard, S, Goldstein, JI, Golimbet, V, Gopal, S, Gratten, J, de Haan, L, Hammer, C, Hamshere, ML, Hansen, M, Hansen, T, Haroutunian, V, Hartmann, AM, Henskens, FA, Herms, S, Hirschhorn, JN, Hoffmann, P, Hofman, A, Hollegaard, MV, Hougaard, DM, Ikeda, M, Joa, I, Julia, A, Kahn, RS, Kalaydjieva, L, Karachanak-Yankova, S, Karjalainen, J, Kavanagh, D, Keller, MC, Kennedy, JL, Khrunin, A, Kim, Y, Klovins, J, Knowles, JA, Konte, B, Kucinskas, V, Kucinskiene, ZA, Kuzelova-Ptackova, H, Kahler, AK, Laurent, C, Keong, JLC, Lee, SH, Legge, SE, Lerer, B, Li, M, Li, T, Liang, K-Y, Lieberman, J, Limborska, S, Loughland, CM, Lubinski, J, Lonnqvist, J, Macek, M, Magnusson, PKE, Maher, BS, Maier, W, Mallet, J, Marsal, S, Mattheisen, M, Mattingsdal, M, McCarley, RW, McDonald, C, McIntosh, AM, Meier, S, Meijer, CJ, Melegh, B, Melle, I, Mesholam-Gately, RI, Metspalu, A, Michie, PT, Milani, L, Milanova, V, Mokrab, Y, Morris, DW, Mors, O, Murphy, KC, Murray, RM, Myin-Germeys, I, Mueller-Myhsok, B, Nelis, M, Nenadic, I, Nertney, DA, Nestadt, G, Nicodemus, KK, Nikitina-Zake, L, Nisenbaum, L, Nordin, A, O'Callaghan, E, O'Dushlaine, C, O'Neill, FA, Oh, S-Y, Olincy, A, Olsen, L, Van Os, J, Pantelis, C, Papadimitriou, GN, Papiol, S, Parkhomenko, E, Pato, MT, Paunio, T, Pejovic-Milovancevic, M, Perkins, DO, Pietilainen, O, Pimm, J, Pocklington, AJ, Powell, J, Price, A, Pulver, AE, Purcell, SM, Quested, D, Rasmussen, HB, Reichenberg, A, Reimers, MA, Richards, AL, Roffman, JL, Roussos, P, Ruderfer, DM, Salomaa, V, Sanders, AR, Schall, U, Schubert, CR, Schulze, TG, Schwab, SG, Scolnick, EM, Scott, RJ, Seidman, LJ, Shi, J, Sigurdsson, E, Silagadze, T, Silverman, JM, Sim, K, Slominsky, P, Smoller, JW, So, H-C, Spencer, CCA, Stahl, EA, Stefansson, H, Steinberg, S, Stogmann, E, Straub, RE, Strengman, E, Strohmaier, J, Stroup, TS, Subramaniam, M, Suvisaari, J, Svrakic, DM, Szatkiewicz, JP, Soderman, E, Thirumalai, S, Toncheva, D, Tosato, S, Veijola, J, Waddington, J, Walsh, D, Wang, D, Wang, Q, Webb, BT, Weiser, M, Wildenauer, DB, Williams, NM, Williams, S, Witt, SH, Wolen, AR, Wong, EHM, Wormley, BK, Xi, HS, Zai, CC, Zheng, X, Zimprich, F, Wray, NR, Stefansson, K, Visscher, PM, Adolfsson, R, Andreassen, OA, Blackwood, DHR, Bramon, E, Buxbaum, JD, Borglum, AD, Cichon, S, Darvasi, A, Domenici, E, Ehrenreich, H, Esko, T, Gejman, PV, Gill, M, Gurling, H, Hultman, CM, Iwata, N, Jablensky, AV, Jonsson, EG, Kendler, KS, Kirov, G, Knight, J, Lencz, T, Levinson, DF, Li, QS, Liu, J, Malhotra, AK, McCarroll, SA, McQuillin, A, Moran, JL, Mortensen, PB, Mowry, BJ, Noethen, MM, Ophoff, RA, Owen, MJ, Palotie, A, Pato, CN, Petryshen, TL, Posthuma, D, Rietschel, M, Riley, BP, Rujescu, D, Sham, PC, Sklar, P, St Clair, D, Weinberger, DR, Wendland, JR, Werge, T, Daly, MJ, Sullivan, PF, and O'Donovan, MC
Abstract: Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.
Published: 2014

16. Additive Genetic Variation in Schizophrenia Risk Is Shared by Populations of African and European Descent

Author: de Candia, TR, Lee, SH, Yang, J, Browning, BL, Gejman, PV, Levinson, DF, Mowry, BJ, Hewitt, JK, Goddard, ME, O'Donovan, MC, Purcell, SM, Posthuma, D, Visscher, PM, Wray, NR, Keller, MC, de Candia, TR, Lee, SH, Yang, J, Browning, BL, Gejman, PV, Levinson, DF, Mowry, BJ, Hewitt, JK, Goddard, ME, O'Donovan, MC, Purcell, SM, Posthuma, D, Visscher, PM, Wray, NR, and Keller, MC
Abstract: To investigate the extent to which the proportion of schizophrenia's additive genetic variation tagged by SNPs is shared by populations of European and African descent, we analyzed the largest combined African descent (AD [n = 2,142]) and European descent (ED [n = 4,990]) schizophrenia case-control genome-wide association study (GWAS) data set available, the Molecular Genetics of Schizophrenia (MGS) data set. We show how a method that uses genomic similarities at measured SNPs to estimate the additive genetic correlation (SNP correlation [SNP-rg]) between traits can be extended to estimate SNP-rg for the same trait between ethnicities. We estimated SNP-rg for schizophrenia between the MGS ED and MGS AD samples to be 0.66 (SE = 0.23), which is significantly different from 0 (p(SNP-rg = 0) = 0.0003), but not 1 (p(SNP-rg = 1) = 0.26). We re-estimated SNP-rg between an independent ED data set (n = 6,665) and the MGS AD sample to be 0.61 (SE = 0.21, p(SNP-rg = 0) = 0.0003, p(SNP-rg = 1) = 0.16). These results suggest that many schizophrenia risk alleles are shared across ethnic groups and predate African-European divergence.
Published: 2013

17. Identifying relationships among genomic disease regions: predicting genes at pathogenic SNP associations and rare deletions.

Author: Storey, JD, Raychaudhuri, S, Plenge, RM, Rossin, EJ, Ng, ACY, International Schizophrenia Consortium, Purcell, SM, Sklar, P, Scolnick, EM, Xavier, RJ, Altshuler, D, Daly, MJ, Storey, JD, Raychaudhuri, S, Plenge, RM, Rossin, EJ, Ng, ACY, International Schizophrenia Consortium, Purcell, SM, Sklar, P, Scolnick, EM, Xavier, RJ, Altshuler, D, and Daly, MJ
Abstract: Translating a set of disease regions into insight about pathogenic mechanisms requires not only the ability to identify the key disease genes within them, but also the biological relationships among those key genes. Here we describe a statistical method, Gene Relationships Among Implicated Loci (GRAIL), that takes a list of disease regions and automatically assesses the degree of relatedness of implicated genes using 250,000 PubMed abstracts. We first evaluated GRAIL by assessing its ability to identify subsets of highly related genes in common pathways from validated lipid and height SNP associations from recent genome-wide studies. We then tested GRAIL, by assessing its ability to separate true disease regions from many false positive disease regions in two separate practical applications in human genetics. First, we took 74 nominally associated Crohn's disease SNPs and applied GRAIL to identify a subset of 13 SNPs with highly related genes. Of these, ten convincingly validated in follow-up genotyping; genotyping results for the remaining three were inconclusive. Next, we applied GRAIL to 165 rare deletion events seen in schizophrenia cases (less than one-third of which are contributing to disease risk). We demonstrate that GRAIL is able to identify a subset of 16 deletions containing highly related genes; many of these genes are expressed in the central nervous system and play a role in neuronal synapses. GRAIL offers a statistically robust approach to identifying functionally related genes from across multiple disease regions--that likely represent key disease pathways. An online version of this method is available for public use (http://www.broad.mit.edu/mpg/grail/).
Published: 2009

18. Genome-wide study of CSF kynurenic acid in bipolar disorder implicates a molecular pathway underlying psychosis

Author: Sellgren, C, primary, Kegel, M, additional, Ekman, CJ, additional, Olsson, SK, additional, Svensson, CI, additional, Hultman, C, additional, Lichtenstein, P, additional, Purcell, SM, additional, Sullivan, PF, additional, Sklar, P, additional, Engberg, G, additional, Erhardt, S, additional, and Landèn, M, additional
Published: 2012
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19. Non-random mating, parent-of-origin, and maternal-fetal incompatibility effects in schizophrenia.

Author: Kim Y, Ripke S, Kirov G, Sklar P, Purcell SM, Owen MJ, O'Donovan MC, Sullivan PF, Kim, Yunjung, Ripke, Stephan, Kirov, George, Sklar, Pamela, Purcell, Shaun M, Owen, Michael J, O'Donovan, Michael C, and Sullivan, Patrick F
Abstract: Although the association of common genetic variation in the extended MHC region with schizophrenia is the most significant yet discovered, the MHC region is one of the more complex regions of the human genome, with unusually high gene density and long-range linkage disequilibrium. The statistical test on which the MHC association is based is a relatively simple, additive model which uses logistic regression of SNP genotypes to predict case-control status. However, it is plausible that more complex models underlie this association. Using a well-characterized sample of trios, we evaluated more complex models by looking for evidence for: (a) non-random mating for HLA alleles, schizophrenia risk profiles, and ancestry; (b) parent-of-origin effects for HLA alleles; and (c) maternal-fetal genotype incompatibility in the HLA. We found no evidence for non-random mating in the parents of individuals with schizophrenia in terms of MHC genotypes or schizophrenia risk profile scores. However, there was evidence of non-random mating that appeared mostly to be driven by ancestry. We did not detect over-transmission of HLA alleles to affected offspring via the general TDT test (without regard to parent of origin) or preferential transmission via paternal or maternal inheritance. We evaluated the hypothesis that maternal-fetal HLA incompatibility may increase risk for schizophrenia using eight classical HLA loci. The most significant alleles were in HLA-B, HLA-C, HLA-DQB1, and HLA-DRB1 but none was significant after accounting for multiple comparisons. We did not find evidence to support more complex models of gene action, but statistical power may have been limiting. [ABSTRACT FROM AUTHOR]
Published: 2013
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20. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways

Author: Anita Thapar, Lena Backlund, Lindsey Kent, Walter J. Muir, A. Jeremy Willsey, Sandra K. Loo, Michael Boehnke, Christa Lese Martin, Ania Korszun, Guiomar Oliveira, Veronica J. Vieland, Stephen W. Scherer, René S. Kahn, Darina Czamara, Jeremy R. Parr, Michael E. Goddard, Willem A. Nolen, Josep Antoni Ramos-Quiroga, Stephen Sanders, Karola Rehnstroem, Nelson B. Freimer, Erin N. Smith, Ann Olincy, Ingrid Melle, Myrna M. Weissman, James A. Knowles, William Byerley, Aravinda Chakravarti, Shaun Purcell, Jens Treutlein, Sebastian Zoellner, Hakon Hakonarson, Susanne Lucae, Markus M. Noethen, Ian B. Hickie, Marion Friedl, Srinivasa Thirumalai, Stephen Newhouse, Joseph Piven, Andrew M. McIntosh, Cathryn M. Lewis, Srdjan Djurovic, Francis J. McMahon, Ayman H. Fanous, Bernie Devlin, Steven A. McCarroll, Alan F. Schatzberg, Peter Szatmari, Marta Ribasés, C. Robert Cloninger, Brenda W.J.H. Penninx, Gerard van Grootheest, Phil Lee, Richard Anney, Elaine K. Green, Geraldine Dawson, Joseph A. Sergeant, Digby Quested, Magdalena Gross, Jack D. Barchas, Nicholas G. Martin, Timothy W. Yu, Jouke-Jan Hottenga, Mark Lathrop, Federica Tozzi, Martin Hautzinger, Alysa E. Doyle, Cinnamon S. Bloss, Sandra Meier, Louise Gailagher, David A. Collier, Farooq Amin, Michael C. Neale, Martin Schalling, Lieuwe de Haan, Bru Cormand, Falk W. Lohoff, Jennifer Crosbie, Howard J. Edenberg, Aarno Palotie, Johannes H. Smit, Robert Freedman, Katherine Gordon-Smith, Michele L. Pergadia, Enda M. Byrne, Hans-Christoph Steinhausen, Benjamin M. Neale, Anjali K. Henders, Michele T. Pato, Manuel Mattheisen, Urban Ösby, Edward M. Scolnick, Evaristus A. Nwulia, Fritz Poustka, Gonneke Willemsen, Andrew C. Heath, David St. Cair, Emma M. Quinn, I. Nicol Ferrier, John R. Kelsoe, Vanessa Hus, Andrew McQuillin, John P. Rice, William M. McMahon, Joseph Biederman, Danyu Lin, Wolfgang Maier, Frans G. Zitman, Josephine Elia, Nicholas J. Schork, Stéphane Jamain, Lizzy Rossin, Jubao Duan, Ingrid Agartz, Devin Absher, Jordan W. Smoller, Matthew W. State, Richard M. Myers, Shrikant Mane, Carlos N. Pato, William E. Bunney, Marian L. Hamshere, Manfred Uhr, Nicholas John Craddock, Astrid M. Vicente, Tobias Banaschewski, David Curtis, Anne Farmer, Scott D. Gordon, Anna K. Kaehler, Eric M. Morrow, Marcella Rietschel, Patrik K. E. Magnusson, Klaus-Peter Lesch, Rebecca McKinney, Jana Strohmaier, Thomas F. Wienker, Pablo V. Gejman, Douglas Blackwood, Maria Helena Pinto de Azevedo, Tiffany A. Greenwood, Don H. Linszen, Daniel L. Koller, Richard Bruggeman, Vinay Puri, Naomi R. Wray, Stanley J. Watson, Elena Maestrini, Valentina Moskvina, Frank Dudbridge, Danielle Posthuma, Edward G. Jones, Lambertus Klei, Sarah E. Bergen, Fan Meng, Steven P. Hamilton, Guy A. Rouleau, Pierandrea Muglia, Mikael Landén, Stephanie H. Witt, Laramie E. Duncan, Stanley Zammit, Judith A. Badner, Florian Holsboer, Eco J. C. de Geus, Daniel Moreno-De-Luca, Benjamin S. Pickard, Gunnar Morken, Michael Conlon O'Donovan, Michael Steffens, Kathryn Roeder, Dorret I. Boomsma, Paul D. Shilling, Stephan Ripke, Nigel Williams, Jeremy M. Silverman, David Craig, Mark J. Daly, Michael Bauer, Detelina Grozeva, Markus J. Schwarz, Peter Holmans, Hugh Gurling, T. Scott Stroup, Aribert Rothenberger, Gary Donohoe, Eric Fombonne, Joseph D. Buxbaum, Matthew Flicldnger, Bryan J. Mowry, Thomas Hansen, Ina Giegling, Grant W. Montgomery, Caroline M. Nievergelt, Susan L. Smalley, Jung-Ying Tzeng, David H. Ledbetter, Christopher A. Walsh, Gerard D. Schellenberg, Sarah E. Medland, Robert D. Oades, James B. Potash, Dan E. Arking, Johannes Schumacher, Michael Gill, James J. McGough, Jennifer L. Moran, Donald W. Black, Sian Caesar, Neelroop N. Parikshak, Ian W. Craig, Sabine M. Klauck, Wade H. Berrettini, T. Foroud, Peter P. Zandi, Inez Myin-Germeys, Marcus Ising, Sven Cichon, Alexandre A. Todorov, Mònica Bayés, Thomas Werge, Susan L. Slager, Stanley I. Shyn, Jim van Os, Derek W. Morris, Douglas M. Ruderfer, Thomas W. Muehleisen, Matthew C. Keller, Susmita Datta, Ian Jones, John B. Vincent, James L. Kennedy, Anthony P. Monaco, Jianxin Shi, Dale R. Nyholt, Bruno Etain, Christine Fraser, Paul Cormican, Miguel Casas, Radhika Kandaswamy, Gerome Breen, Stephen V. Faraone, Jonna Kuntsi, Thomas Bettecken, Witte J.G. Hoogendijk, Nancy G. Buccola, Franziska Degenhardt, Lyudmila Georgieva, Marion Leboyer, Alan R. Sanders, John Strauss, Dan Rujescu, Russell Schachar, Helena Medeiros, Lisa Jones, Peter M. Visscher, Lauren A. Weiss, René Breuer, John I. Nurnberger, Andreas Reif, Phoenix Kwan, Vihra Milanova, Chunyu Liu, Martin A. Kohli, Donald J. MacIntyre, Nicholas Bass, Khalid Choudhury, Edwin H. Cook, Catherine Lord, Andrew D. Paterson, Jobst Meyer, Richard P. Ebstein, Zhaoming Zhao, Niklas Laengstroem, Thomas G. Schulze, Peter Propping, Wei Xu, Robert C. Thompson, Kimberly Chambert, Jonathan Pimm, Ivan Nikolov, Pamela A. F. Madden, Kevin A. McGhee, Jacob Lawrence, Jan K. Buitelaar, Andres Ingason, Christine M. Freitag, Robert Krasucki, Wiepke Cahn, Rita M. Cantor, Christina M. Hultman, Melvin G. McInnis, Catalina Betancur, Eftichia Duketis, Michael T. Murtha, Thomas H. Wassink, Philip Asherson, John S. Witte, Elaine Kenny, Edmund J.S. Sonuga-Barke, Lydia Krabbendam, Line Olsen, Agatino Battaglia, Laura J. Scott, Annette M. Hartmann, Yunjung Kim, Richard O. Day, Edwin J. C. G. van den Oord, Ole A. Andreassen, Herbert Roeyers, Michael John Owen, Colm O'Dushlaine, Peng Zhang, Morten Mattingsdal, Michael L. Cuccaro, Margaret A. Pericak-Vance, Joachim Hallmayer, Jun Li, Pamela B. Mahon, Elisabeth B. Binder, William A. Scheftner, Daniel H. Geschwind, Christel M. Middeldorp, Josef Frank, Keith Matthews, Jennifer K. Lowe, Paul Lichtenstein, Verneri Anttila, Pamela Sklar, Szabocls Szelinger, Roel A. Ophoff, Peter McGuffin, Stefan Herms, Bettina Konte, George Kirov, Hilary Coon, Maria Hipolito, Louise Frisén, Kenneth S. Kendler, Frank Bellivier, James S. Sutdiffe, Jeffrey A. Lieberman, Todd Lencz, Susanne Hoefels, Alan W. McLean, Barbara Franke, Huda Akil, Soumya Raychaudhuri, Ellen M. Wijsman, Vishwajit L. Nimgaonkar, Roy H. Perlis, Patrick J. McGrath, Susan L. Santangelo, William Coryell, Henrik B. Rasmussen, Weihua Guan, William Lawson, Elliot S. Gershon, Sean Ennis, Aiden Corvin, Allan H. Young, Thomas B. Barrett, Jonathan L. Haines, Douglas F. Levinson, Ana Miranda, Anil K. Malhotra, S. Hong Lee, Stan F. Nelson, Anthony J. Bailey, Patrick F. Sullivan, Dorothy E. Grice, Lefkos T. Middleton, Bertram Mueller-Myhsok, Michael R. Barnes, Adebayo Anjorin, O'Dushlaine, C, Rossin, L, Lee, Ph, Duncan, L, Parikshak, Nn, Newhouse, S, Ripke, S, Neale, Bm, Purcell, Sm, Posthuma, D, Nurnberger, Ji, Lee, Sh, Faraone, Sv, Perlis, Rh, Mowry, Bj, Thapar, A, Goddard, Me, Witte, J, Absher, D, Agartz, I, Akil, H, Amin, F, Andreassen, Oa, Anjorin, A, Anney, R, Anttila, V, Arking, De, Asherson, P, Azevedo, Mh, Backlund, L, Badner, Ja, Bailey, Aj, Banaschewski, T, Barchas, Jd, Barnes, Mr, Barrett, Tb, Bass, N, Battaglia, A, Bauer, M, Bayés, M, Bellivier, F, Bergen, Se, Berrettini, W, Betancur, C, Bettecken, T, Biederman, J, Binder, Eb, Black, Dw, Blackwood, Dh, Bloss, C, Boehnke, M, Boomsma, Di, Breuer, R, Bruggeman, R, Cormican, P, Buccola, Ng, Buitelaar, Jk, Bunney, We, Buxbaum, Jd, Byerley, Wf, Byrne, Em, Caesar, S, Cahn, W, Cantor, Rm, Casas, M, Chakravarti, A, Chambert, K, Choudhury, K, Cichon, S, Mattheisen, M, Cloninger, Cr, Collier, Da, Cook, Eh, Coon, H, Cormand, B, Corvin, A, Coryell, Wh, Craig, Dw, Craig, Iw, Crosbie, J, Cuccaro, Ml, Curtis, D, Czamara, D, Datta, S, Dawson, G, Day, R, De Geus, Ej, Degenhardt, F, Djurovic, S, Donohoe, Gj, Doyle, Ae, Duan, J, Dudbridge, F, Duketis, E, Ebstein, Rp, Edenberg, Hj, Elia, J, Ennis, S, Etain, B, Fanous, A, Farmer, Ae, Ferrier, In, Flickinger, M, Fombonne, E, Foroud, T, Frank, J, Franke, B, Fraser, C, Freedman, R, Freimer, Nb, Freitag, Cm, Friedl, M, Frisén, L, Gallagher, L, Gejman, Pv, Georgieva, L, Gershon, E, Giegling, I, Gill, M, Gordon, Sd, Gordon-Smith, K, Green, Ek, Greenwood, Ta, Grice, De, Gross, M, Grozeva, D, Guan, W, Gurling, H, De Haan, L, Haines, Jl, Hakonarson, H, Hallmayer, J, Hamilton, Sp, Hamshere, Ml, Hansen, Tf, Hartmann, Am, Hautzinger, M, Heath, Ac, Henders, Ak, Herms, S, Hickie, Ib, Hipolito, M, Hoefels, S, Holsboer, F, Hoogendijk, Wj, Hottenga, Jj, Hultman, Cm, Hus, V, Ingason, A, Ising, M, Jamain, S, Jones, Eg, Jones, I, Jones, L, Tzeng, Jy, Kähler, Ak, Kahn, R, Kandaswamy, R, Keller, Mc, Kennedy, Jl, Kenny, E, Kent, L, Kim, Y, Kirov, Gk, Klauck, Sm, Klei, L, Knowles, Ja, Kohli, Ma, Koller, Dl, Konte, B, Korszun, A, Krabbendam, L, Krasucki, R, Kuntsi, J, Kwan, P, Landén, M, Längström, N, Lathrop, M, Lawrence, J, Lawson, Wb, Leboyer, M, Ledbetter, Dh, Lencz, T, Lesch, Kp, Levinson, Df, Lewis, Cm, Li, J, Lichtenstein, P, Lieberman, Ja, Lin, Dy, Linszen, Dh, Liu, C, Lohoff, Fw, Loo, Sk, Lord, C, Lowe, Jk, Lucae, S, Macintyre, Dj, Madden, Pa, Maestrini, E, Magnusson, Pk, Mahon, Pb, Maier, W, Malhotra, Ak, Mane, Sm, Martin, Cl, Martin, Ng, Matthews, K, Mattingsdal, M, Mccarroll, Sa, Mcghee, Ka, Mcgough, Jj, Mcgrath, Pj, Mcguffin, P, Mcinnis, Mg, Mcintosh, A, Mckinney, R, Mclean, Aw, Mcmahon, Fj, Mcmahon, Wm, Mcquillin, A, Medeiros, H, Medland, Se, Meier, S, Melle, I, Meyer, J, Middeldorp, Cm, Middleton, L, Milanova, V, Miranda, A, Monaco, A, Montgomery, Gw, Moran, Jl, Moreno-De-Luca, D, Morken, G, Morris, Dw, Morrow, Em, Moskvina, V, Muglia, P, Mühleisen, Tw, Muir, Wj, Müller-Myhsok, B, Murtha, M, Myers, Rm, Myin-Germeys, I, Neale, Mc, Nelson, Sf, Nievergelt, Cm, Nikolov, I, Nimgaonkar, V, Nolen, Wa, Nöthen, Mm, Nwulia, Ea, Nyholt, Dr, Oades, Rd, Olincy, A, Oliveira, G, Olsen, L, Ophoff, Ra, Osby, U, Owen, Mj, Palotie, A, Parr, Jr, Paterson, Ad, Pato, Cn, Pato, Mt, Penninx, Bw, Pergadia, Ml, Pericak-Vance, Ma, Pickard, B, Pimm, J, Piven, J, Potash, Jb, Poustka, F, Propping, P, Puri, V, Quested, Dj, Quinn, Em, Ramos-Quiroga, Ja, Rasmussen, Hb, Raychaudhuri, S, Rehnström, K, Reif, A, Ribasés, M, Rice, Jp, Rietschel, M, Roeder, K, Roeyers, H, Rothenberger, A, Rouleau, G, Ruderfer, D, Rujescu, D, Sanders, Ar, Sanders, Sj, Santangelo, Sl, Sergeant, Ja, Schachar, R, Schalling, M, Schatzberg, Af, Scheftner, Wa, Schellenberg, Gd, Scherer, Sw, Schork, Nj, Schulze, Tg, Schumacher, J, Schwarz, M, Scolnick, E, Scott, Lj, Shi, J, Shilling, Pd, Shyn, Si, Silverman, Jm, Slager, Sl, Smalley, Sl, Smit, Jh, Smith, En, Sonuga-Barke, Ej, St Clair, D, State, M, Steffens, M, Steinhausen, Hc, Strauss, J, Strohmaier, J, Stroup, T, Sutcliffe, J, Szatmari, P, Szelinger, S, Thirumalai, S, Thompson, Rc, Todorov, Aa, Tozzi, F, Treutlein, J, Uhr, M, van den Oord, Jc, Van Grootheest, G, Van Os, J, Vicente, A, Vieland, Vj, Vincent, Jb, Visscher, Pm, Walsh, Ca, Wassink, Th, Watson, Sj, Weissman, Mm, Werge, T, Wienker, Tf, Wijsman, Em, Willemsen, G, Williams, N, Willsey, Aj, Witt, Sh, Xu, W, Young, Ah, Yu, Tw, Zammit, S, Zandi, Pp, Zhang, P, Zitman, Fg, Zöllner, S, Devlin, B, Kelsoe, Jr, Sklar, P, Daly, Mj, O'Donovan, Mc, Craddock, N, Kendler, K, Weiss, La, Wray, Nr, Zhao, Z, Geschwind, Dh, Sullivan, Pf, Smoller, Jw, Holmans, Pa, Breen, G., Génétique de l'autisme = Genetics of Autism (NPS-01), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Human genetics, Psychiatry, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Mental health, Child and Adolescent Psychiatry / Psychology, Epidemiology, Gastroenterology & Hepatology, Hematology, University of St Andrews. School of Medicine, University of St Andrews. Institute of Behavioural and Neural Sciences, Psychiatrie & Neuropsychologie, MUMC+: MA Psychiatrie (3), MUMC+: Hersen en Zenuw Centrum (3), RS: MHeNs - R2 - Mental Health, ANS - Amsterdam Neuroscience, Adult Psychiatry, Child Psychiatry, Universitat de Barcelona, Perceptual and Cognitive Neuroscience (PCN), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Complex Trait Genetics, Biological Psychology, Educational Neuroscience, Clinical Neuropsychology, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, LEARN! - Social cognition and learning, LEARN! - Brain, learning and development, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Mental Health, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), O'Dushlaine, Colm, Rossin, Lizzy, Lee, Phil H, Duncan, Laramie, Lee, S Hong, Breen, Gerome, International Inflammatory Bowel Disease Genetics Consortium (IIBDGC), Network and Pathway Analysis Subgroup of the Psychiatric Genomics Consortium, and Myin-Germeys, Inez
Subjects: Netherlands Twin Register (NTR), Statistical methods, Autism, Medizin, LOCI, Genome-wide association study, heritability, Genome-wide association studies, Histones, Genètica mèdica, 0302 clinical medicine, Histone methylation, Databases, Genetic, 2.1 Biological and endogenous factors, Psychology, GWAS, Aetiology, Psychiatric genetics, R2C, bipolar disorder, Psychiatry, 0303 health sciences, Disorders, Loci, Depression, General Neuroscience, Mental Disorders, Medical genetics, METHYLATION, Brain, 3rd-DAS, Serious Mental Illness, Psychiatric Disorders, 3. Good health, Histone, Mental Health, Schizophrenia, Mental Disorder, Cognitive Sciences, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Promoters, BDC, BURDEN, RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry, Human, Signal Transduction, medicine.medical_specialty, DISORDERS, Genomics, Network and Pathway Analysis Subgroup of Psychiatric Genomics Consortium, Burden, Biology, Methylation, Article, Biological pathway, PROMOTERS, 03 medical and health sciences, Databases, Genetic, medicine, Genetics, Humans, Genetic Predisposition to Disease, histone methylation, Bipolar disorder, Psiquiatria, AUTISM, 030304 developmental biology, Genetic association, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Neurology & Neurosurgery, Neuroscience (all), Human Genome, Neurosciences, medicine.disease, Brain Disorders, Good Health and Well Being, DE-NOVO MUTATIONS, Perturbações do Desenvolvimento Infantil e Saúde Mental, RC0321, Genome-wide Association Studies, De-novo mutations, major depression, Neuroscience, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: G.B. and S.N. acknowledge funding support for this work from the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. P.H.L. is supported by US National Institute of Mental Health (NIMH) grant K99MH101367. Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders. Postprint
Published: 2015
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21. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs

Author: Laura J. Scott, Bernie Devlin, Steven A. McCarroll, James S. Sutcliffe, Stefan Herms, Yunjung Kim, Richard O. Day, Thomas F. Wienker, Frank Dudbridge, I. Nicol Ferrier, Bettina Konte, Marta Ribasés, C. Robert Cloninger, Brenda W.J.H. Penninx, Detelina Grozeva, Herbert Roeyers, Peter Holmans, Colm O'Dushlaine, Scott D. Gordon, Sarah E. Bergen, Fan Meng, Morten Mattingsdal, Hugh Gurling, Ina Giegling, Gerard van Grootheest, Ania Korszun, Markus J. Schwarz, George Kirov, Sebastian Zöllner, Kenneth S. Kendler, Nicholas G. Martin, Michael Conlon O'Donovan, Michael C. Neale, Jim van Os, Aravinda Chakravarti, Timothy W. Yu, Mikael Landén, Inez Myin-Germeys, Markus M. Nöthen, Kathryn Roeder, James B. Potash, Alan W. McLean, Louise Gallagher, Anna K. Kähler, Thomas Bettecken, Nigel Williams, Frank Bellivier, Joseph D. Buxbaum, Derek W. Morris, Susan L. Smalley, Jung-Ying Tzeng, Martin Schalling, Douglas M. Ruderfer, Caroline M. Nievergelt, T. Scott Stroup, David H. Ledbetter, Jennifer Crosbie, Anita Thapar, Barbara Franke, Jeffrey A. Lieberman, Huda Akil, Miguel Casas, Daniel H. Geschwind, Paul Cormican, Bertram Müller-Myhsok, Lyudmila Georgieva, Robert Krasucki, Martin Hautzinger, Alysa E. Doyle, Cinnamon S. Bloss, Gerard D. Schellenberg, Todd Lencz, Melvin G. McInnis, Catalina Betancur, Josep Antoni Ramos-Quiroga, Stephen Sanders, Eftichia Duketis, Don H. Linszen, Matthew W. State, Richard M. Myers, Soumya Raychaudhuri, Lizzy Rossin, Howard J. Edenberg, Michael E. Goddard, S. Hong Lee, Elisabeth B. Binder, Pablo V. Gejman, William A. Scheftner, Wolfgang Maier, Judith A. Badner, Christel M. Middeldorp, Maria Helena Pinto de Azevedo, Johannes H. Smit, Willem A. Nolen, Lieuwe de Haan, Gonneke Willemsen, Keith Matthews, Ellen M. Wijsman, Jennifer K. Lowe, Rebecca McKinney, Magdalena Gross, Dorothy E. Grice, James A. Knowles, Andrew C. Heath, Jana Strohmaier, Vishwajit L. Nimgaonkar, William Byerley, William E. Bunney, Dan E. Arking, Andrew McQuillin, William M. McMahon, Manuel Mattheisen, Hans-Christoph Steinhausen, Joseph Biederman, Guy A. Rouleau, James J. McGough, Sian Caesar, Edward M. Scolnick, Lefkos T. Middleton, Jack D. Barchas, Ian B. Hickie, Danyu Lin, Patrik K. E. Magnusson, Douglas Blackwood, Francis J. McMahon, Ingrid Agartz, Elena Maestrini, Marian L. Hamshere, Lindsey Kent, Walter J. Muir, Stephan Ripke, Lydia Krabbendam, Christine Fraser, Maria Hipolito, Louise Frisén, Eric Fombonne, Emma M. Quinn, Michael Bauer, Richard P. Ebstein, Michael Steffens, Jordan W. Smoller, Stanley J. Watson, Michael Boehnke, Philip Asherson, Agatino Battaglia, Elliot S. Gershon, Russell Schachar, Marcus Ising, Peng Zhang, Margaret A. Pericak-Vance, Joachim Hallmayer, Sean Ennis, Radhika Kandaswamy, René S. Kahn, Susanne Hoefels, Thomas W. Mühleisen, Pamela Sklar, Paul Lichtenstein, Verneri Anttila, Michael L. Cuccaro, Florian Holsboer, René Breuer, Eric M. Morrow, Vinay Puri, Naomi R. Wray, Szabocls Szelinger, Sabine M. Klauck, John B. Vincent, Shrikant Mane, Aribert Rothenberger, Marion Friedl, Ian Jones, Khalid Choudhury, Michael R. Barnes, Adebayo Anjorin, Edwin H. Cook, William Lawson, Allan H. Young, Lambertus Klei, Bryan J. Mowry, Johannes Schumacher, Michael Gill, James L. Kennedy, Marcella Rietschel, Aiden Corvin, Henrik B. Rasmussen, Susmita Datta, Kimberly Chambert, Daniel Moreno-De-Luca, Benjamin S. Pickard, Stan F. Nelson, Veronica J. Vieland, Stephen W. Scherer, Peter M. Visscher, John Strauss, Andreas Reif, Andrew D. Paterson, Ann Olincy, Phoenix Kwan, Anthony J. Bailey, Patrick F. Sullivan, Pierandrea Muglia, Gunnar Morken, Susanne Lucae, Ayman H. Fanous, Jacob Lawrence, Donald J. MacIntyre, Nancy G. Buccola, Rita M. Cantor, Christina M. Hultman, Weihua Guan, Anthony P. Monaco, Jouke-Jan Hottenga, Elaine Kenny, Jianxin Shi, Dale R. Nyholt, Kevin A. McGhee, Falk W. Lohoff, Jonna Kuntsi, Niklas Långström, John I. Nurnberger, Nelson B. Freimer, Erin N. Smith, John P. Rice, Michael T. Murtha, Thomas H. Wassink, Alexandre A. Todorov, Edmund J.S. Sonuga-Barke, Dan Rujescu, Roy H. Perlis, John S. Witte, Christopher A. Walsh, Matthew C. Keller, Pamela B. Mahon, Patrick J. McGrath, Susan L. Santangelo, Annette M. Hartmann, Ole A. Andreassen, Tatiana Foroud, Shaun Purcell, Josef Frank, Douglas F. Levinson, William Coryell, Ana Miranda, Alan F. Schatzberg, Peter Szatmari, Jun Li, Gerome Breen, Stephen V. Faraone, Anil K. Malhotra, Helena Medeiros, Martin A. Kohli, Nicholas Bass, Catherine Lord, Peter Propping, Wei Xu, Federica Tozzi, Ivan Nikolov, Jan K. Buitelaar, Thomas G. Schulze, Katherine Gordon-Smith, Michele L. Pergadia, Fritz Poustka, Valentina Moskvina, David Curtis, Tobias Banaschewski, Devin Absher, Danielle Posthuma, Stanley Zammit, Gary Donohoe, Ingrid Melle, Karola Rehnström, Thomas Hansen, Myrna M. Weissman, Stanley I. Shyn, Hakon Hakonarson, Christa Lese Martin, Digby Quested, Darina Czamara, Jeremy R. Parr, Pamela A. F. Madden, Jens Treutlein, Aarno Palotie, Robert Freedman, Sandra Meier, Bru Cormand, Nicholas J. Schork, Michele T. Pato, John R. Kelsoe, Vanessa Hus, Frans G. Zitman, Josephine Elia, David St Clair, Roel A. Ophoff, Peter McGuffin, Jonathan Pimm, Jonathan L. Haines, Wiepke Cahn, Matthew Flickinger, Steven P. Hamilton, Michael John Owen, Paul D. Shilling, Jeremy M. Silverman, David Craig, Mark J. Daly, Sarah E. Medland, Robert D. Oades, Marion Leboyer, Alan R. Sanders, Vihra Milanova, Chunyu Liu, Jobst Meyer, Dorret I. Boomsma, Evaristus A. Nwulia, Thomas B. Barrett, Jennifer L. Moran, Donald W. Black, Mònica Bayés, Witte J.G. Hoogendijk, Franziska Degenhardt, Benjamin M. Neale, Daniel L. Koller, Carlos N. Pato, Nicholas John Craddock, Richard Bruggeman, Enda M. Byrne, Edward G. Jones, Eco J. C. de Geus, Stéphane Jamain, Jubao Duan, Anne Farmer, Astrid M. Vicente, Grant W. Montgomery, Thomas Werge, Cathryn M. Lewis, Srdjan Djurovic, Phil Lee, Richard Anney, Elaine K. Green, Wade H. Berrettini, Peter P. Zandi, Susan L. Slager, Stephanie H. Witt, Ian W. Craig, Lisa Jones, Sven Cichon, Bruno Etain, Mark Lathrop, Hilary Coon, Robert C. Thompson, Lena Backlund, A. Jeremy Willsey, Andres Ingason, Christine M. Freitag, Sandra K. Loo, Guiomar Oliveira, Line Olsen, Edwin J. C. G. van den Oord, Geraldine Dawson, Joseph A. Sergeant, David A. Collier, Farooq Amin, Srinivasa Thirumalai, Manfred Uhr, Joseph Piven, Andrew M. McIntosh, Anjali K. Henders, Urban Ösby, Klaus-Peter Lesch, Tiffany A. Greenwood, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Perceptual and Cognitive Neuroscience (PCN), Lee, S Hong, Ripke, Stephan, Neale, Benjamin M, Faraone, Stephen V, Wray, Naomi R, Cross-Disorder Group of the Psychiatric Genomics Consortium, International Inflammatory Bowel Disease Genetics Consortium (IIBDGC), Queensland Brain Institute, University of Queensland [Brisbane], Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], SUNY Upstate Medical University, State University of New York (SUNY), Mount Sinai School of Medicine, Department of Psychiatry-Icahn School of Medicine at Mount Sinai [New York] (MSSM), Psychiatric and Neurodevelopmental Genetics Unit, Queensland Centre for Mental Health Research, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, MRC Centre for Neuropsychiatric Genetics and Genomics, Medical Research Council (MRC)-School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff], New South Wales Department of Primary Industries (NSW DPI), Faculty of Land and Food Resources, University of Melbourne, HudsonAlpha Institute for Biotechnology [Huntsville, AL], Institute of Clinical Medicine [Oslo], Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Diakonhjemmet Hospital, University of Michigan [Ann Arbor], University of Michigan System, Molecular and Behavioral Neuroscience Institute (MBNI), University of Michigan System-University of Michigan System, Emory University [Atlanta, GA], Oslo University Hospital [Oslo], University College of London [London] (UCL), Trinity College Dublin, Johns Hopkins University School of Medicine [Baltimore], MRC Social Genetic Developmental and Psychiatry Centre, Institute of Psychiatry, King's College London, University of Coimbra [Portugal] (UC), Karolinska Institutet [Stockholm], University of Chicago, University of British Columbia (UBC), Department of Child and Adolescent Psychiatry and Psychotherapy [Mannheim], Universität Heidelberg [Heidelberg] = Heidelberg University, Weill Medical College of Cornell University [New York], GlaxoSmithKline, Glaxo Smith Kline, Portland Veterans Administration Medical Center, Windeyer Institute for Medical Sciences, IRCCS Fondazione Stella Maris [Pisa], University Hospital Carl Gustav Carus [Dresden, Germany], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Centro Nacional de Analisis Genomico [Barcelona] (CNAG), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), European Network of Bipolar Research Expert Centres (ENBREC), ENBREC, Department of Psychiatry [Philadelphia], University of Pennsylvania, Physiopathologie des Maladies du Système Nerveux Central, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de recherche Phytopharmacie et Médiateurs Chimiques (UPMC), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, Massachusetts General Hospital [Boston, MA, USA], University of Iowa [Iowa City], University of Edinburgh, Royal Hospital for Sick Children [Edinburgh], The Scripps Research Institute [La Jolla, San Diego], MRC Social, Genetic and Developmental Psychiatry Centre (SGDP), King‘s College London-The Institute of Psychiatry, Institute of Medical Sciences, University of Aberdeen, Social, Genetic and Developmental Psychiatry Centre (SGDP), King‘s College London, Department of Genetic Epidemiology in Psychiatry [Mannhein], Universität Heidelberg [Heidelberg] = Heidelberg University-Central Institute of Mental Health Mannheim, Department of Psychiatry, University of Groningen [Groningen]-University Medical Center Groningen [Groningen] (UMCG), Trinity College Dublin-St. James's Hospital, School of Nursing, Louisiana State University (LSU), Donders Center for Cognitive Neuroimaging, Donders Centre for Cognitive Neuroimaging, Radboud University [Nijmegen]-Radboud University [Nijmegen], Department of Psychiatry and Human Behavior, University of California [Irvine] (UC Irvine), University of California (UC)-University of California (UC), Friedman Brain Institute, Mount Sinai, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Seaver Autism Center for Research and Treatment, Department of Neuroscience, Departments of Psychiatry, Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai [New York] (MSSM)-Seaver Autism Center-, The Mindich Child Health & Development Institute, Friedman Brain Institute, The Mindich Child Health and Development Institute, University of California [San Francisco] (UC San Francisco), Department of Psychiatry, School of Clinical and Experimental Medicine, University of Alabama at Birmingham [ Birmingham] (UAB), Department of Human Genetics, Los Angeles, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC)-University of California [Los Angeles] (UCLA), McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Stanley Center for Psychiatric Research, Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Mental Health Sciences Unit, Department of Genomics, Life and Brain Center, Universität Bonn = University of Bonn, Institute of Human Genetics, Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Academic Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Department of Disability and Human Development, University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, Department of Developmental Neuroscience, Neuropsychiatric Genetics Research Group, University of California [San Diego] (UC San Diego), John P. Hussman Institute for Human Genomics, University of Miami [Coral Gables], East London NHS Foundation Trust, Queen Mary University of London (QMUL), Max-Planck-Institut für Psychiatrie, Genetics Institute, Autism Speaks and the Department of Psychiatry, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), School of Neurology, Neurobiology and Psychiatry, Royal Victoria Infirmary, Medstar Research Institute, KG Jebsen Centre for Psychosis Research, University of Oslo (UiO)-Institute of Clinical Medicine-Oslo University Hospital [Oslo], Deparment of Medical Genetics, Human Genetics Branch, National Institutes of Health [Bethesda] (NIH)-National Institute of Mental Health (NIMH), Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Department of Psychiatry and Behavioral Sciences, University of Chicago-NorthShore University Health System, Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine (LSHTM), Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe-Universität Frankfurt am Main, Psychology Department, National University of Singapore (NUS), Department of Biochemistry and Molecular Biology, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indiana University System-Indiana University System, Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University (VCU), University of Dundee School of Medicine, University of Dundee, Department of Biostatistics and Center for Statistical Genetics, University of Michigan System-University of Michigan System-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU), Department of Child Psychiatry, McGill University = Université McGill [Montréal, Canada]-Montreal Children's Hospital, McGill University Health Center [Montreal] (MUHC)-McGill University Health Center [Montreal] (MUHC), Howard University College of Medicine, University of Colorado [Denver], Center for Neurobehavioral Genetics, Department of Genomics, Department of Molecular Medicine, Department of Neurology, University of California (UC)-University of California (UC)-David Geffen School of Medicine [Los Angeles], Medical Research Council-Cardiff University, Department of Psychiatry [Pittsburgh], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Fisico-Quimica Biologica, Universidade Federal do Rio de Janeiro (UFRJ), Vanderbilt Brain Institute, Vanderbilt University School of Medicine [Nashville], Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania-University of Pennsylvania-Children’s Hospital of Philadelphia (CHOP ), The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Institute for Human Genetics, Neurosciences Centre of Excellence in Drug Discovery, GlaxoSmithKline Research and Development, Center for Genomic Medicine, Copenhagen University Hospital-Rigshospitalet [Copenhagen], Copenhagen University Hospital, Department of Clinical and Developmental Psychology, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Clinical Research Unit, Brain & Mind Research Institute-The University of Sydney, Functional Genomics, Neuronal Plasticity / Mouse Behaviour, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Department of Medical Epidemiology and Biostatistics (MEB), Autism and Communicative Disorders Centre, Center for Human Genetic Research, Center for neuroscience-University of California [Davis] (UC Davis), Bioinformatics Research Center, North Carolina State University [Raleigh] (NC State), Norwegian University of Science and Technology [Trondheim] (NTNU), Norwegian University of Science and Technology (NTNU)-Norwegian University of Science and Technology (NTNU), Emory University [Atlanta, GA]-Atlanta Veterans Affairs Medical Center, Psychiatric Neurogenetics Section, Centre for Addiction and Mental Health, School of Medicine, University of St Andrews [Scotland], Institute of Human Genetics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Division of Molecular Genome Analysis, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Department of Ecology and Evolutionary Biology, Insitute of Neuroscience and Physiology, University of Gothenburg (GU), Institut de Génomique d'Evry (IG), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Developmental Brain and Behaviour Unit, University of Southampton, Division of Psychiatric Genomics, Rheinische Friedrich-Wilhelms-Universität Bonn, Statistical Genetics Group, Department of Human Genetics, Department of Pharmacy and Biotechnology, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Department of Psychiatry and Psychotherapy, Department of Mental Health, Johns Hopkins University and Hospital, W.M. Keck Biotechnology Resource Laboratory, Yale University [New Haven], Institutes of Neuroscience and Health and Society, Newcastle University [Newcastle], Genetic Epidemiology Unit, Queensland Institute of Medical Research, Department of Biomedicine and the Centre for Integrative Sequencing, Aarhus University [Aarhus], Sorlandet Hospital HF, Division of Psychiatry, University of Edinburgh-Royal Edinburgh Hospital, Medical Genetics Section, University of Edinburgh-Western General Hospital, Unit on the Genetic Basis of Mood and Anxiety Disorders, National Institutes of Health [Bethesda] (NIH), Unidade de Neurodesenvolvimento e Autismo (UNDA), Hospital Pediatrico de Coimbra, Division of Mental Health and Addiction, Molecular Psychiatry Laboratory, University of Michigan System-University of Michigan System-Molecular and Behavioral Neuroscience Institute, Research and Development, First Psychiatric Clinic-Alexander University Hospital, Registo Oncológico Regional-Sul, Instituto Português de Oncologia de Francisco Gentil, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford, St. Olav's Hospital, Brown University, Department of Molecular Biology, Cell Biology and Biochemistry, Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig-Universität Leipzig, Human Genetics Department, University of Pittsburgh (PITT), Institute for Biomedical Imaging and Life Science, University Medical Center [Utrecht]-Brain Center Rudolf Magnus, Head of Medical Sequencing, Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, The Centre for Applied Genomics, Toronto, The Hospital for sick children [Toronto] (SickKids)-University of Toronto-Department of Molecular Genetics-McLaughlin Centre, Carolina Institute for Developmental Disabilities, Analytic and Translational Genetics Unit, Rush University Medical Center [Chicago], Julius-Maximilians-Universität Würzburg (JMU), Washington University in Saint Louis (WUSTL), Department of Statistics, Carnegie Mellon University [Pittsburgh] (CMU), Department of Experimental Clinical and Health Psychology, Universiteit Gent = Ghent University (UGENT), Department of Child and Adolescent Psychiatry, Georg-August-University = Georg-August-Universität Göttingen, Department of Medicine, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CR CHUM), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM)-Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM), Departments of Psychiatry and Genetics, Yale School of Medicine [New Haven, Connecticut] (YSM), Maine Medical Center, Free University of Amsterdam, Department of Psychiatry and Behavioral Sciences [Stanford], Pathology and Laboratory Medicine, The Scripps Translational Science Institute and The Scripps Research Institute, Psychiatric Center Nordbaden, Division of Cancer Epidemiology and Genetics, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), The Scripps Translational Science Institute and Scripps Health, Child and Adolescent Psychiatry, Aarhus University Hospital, Molecular Neuropsychiatry and Development Laboratory, Department of Molecular Physiology & Biophysics and Psychiatry, Vanderbilt University [Nashville]-Centers for Human Genetics Research and Molecular Neuroscience, Department of Psychiatry and Behavioural Neurosciences, McMaster University [Hamilton, Ontario]-Offord Centre for Child Studies, The Translational Genomics Research Institute (TGen), Oxford Health NHS Foundation Trust, Marlborough House Secure Unit, Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal] (INSA), BioFIG, Center for Biodiversity, Functional and Integrative Genomics, Battelle Center for Mathematical Medicine, Ohio State University [Columbus] (OSU)-Nationwide Children's Hospital, University of Toronto, Diamantina Institute, Carver College of Medicine [Iowa City], University of Iowa [Iowa City]-University of Iowa [Iowa City], Departments of Biostatistics and Medicine, University of Washington [Seattle], ArcelorMittal Maizières Research SA, ArcelorMittal, Institute of Mental Health, Johns Hopkins Bloomberg School of Public Health [Baltimore], Johns Hopkins University (JHU)-Johns Hopkins University (JHU), Psychiatrie & Neuropsychologie, Farmacologie en Toxicologie, RS: CARIM School for Cardiovascular Diseases, RS: MHeNs School for Mental Health and Neuroscience, Biological Psychology, Educational Neuroscience, Clinical Neuropsychology, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, LEARN! - Social cognition and learning, Biophotonics and Medical Imaging, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, LEARN! - Brain, learning and development, EMGO+ - Mental Health, LEARN!, Neuroscience Campus Amsterdam - Brain Imaging Technology, LaserLaB - Biophotonics and Microscopy, State University of New York (SUNY)-State University of New York (SUNY), Department of Neuroscience and Physiology, Faculty of Land and Environment, Biosciences Research Division, Department of Environment and Primary Industries Victoria, Department of Epidemiology and Biostatistics, University of California [San Francisco] (UCSF), University of California-University of California, Universität Heidelberg [Heidelberg], Cornell University [New York]-Weill Medical College of Cornell University [New York], Bioinformatics, Internal Medicine, Portland Va Medical Center : Ganzini Linda MD, Technische Universität Dresden = Dresden University of Technology (TU Dresden)-University Hospital Carl Gustav Carus, Centro Nacional de Análisis Genómico (CNAG), Parc Científic de Barcelona (PCB), University of Pennsylvania [Philadelphia], Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Clinical and Research Programs in Pediatric Psychopharmacology and Adult ADHD, Division Genetic Epidemiology in Psychiatry, Central Institute of Mental Health [Mannheim], Medical Faculty [Mannheim]-Medical Faculty [Mannheim], Universität Heidelberg [Heidelberg]-Central Institute of Mental Health Mannheim, Radboud university [Nijmegen]-Radboud university [Nijmegen], University of California [Irvine] (UCI), University of California-University of California-University of California [Los Angeles] (UCLA), University of Bonn, University of California-University of California-David Geffen School of Medicine [Los Angeles], Cardiff University-Medical Research Council, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia]-Children’s Hospital of Philadelphia (CHOP ), Bureau d'Économie Théorique et Appliquée (BETA), Institut National de la Recherche Agronomique (INRA)-Université de Strasbourg (UNISTRA)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, University of Oxford [Oxford], Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], University of Toronto-The Hospital for sick children [Toronto] (SickKids)-Department of Molecular Genetics-McLaughlin Centre, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Universiteit Gent = Ghent University [Belgium] (UGENT), University of Göttingen - Georg-August-Universität Göttingen, Yale University School of Medicine, Georg-August-University [Göttingen], ANS - Amsterdam Neuroscience, Adult Psychiatry, Child Psychiatry, Psychiatry, Human genetics, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Mental health, NCA - Brain imaging technology, Lee SH, Ripke S, Neale BM, Faraone SV, Purcell SM, Perlis RH, Mowry BJ, Thapar A, Goddard ME, Witte JS, Absher D, Agartz I, Akil H, Amin F, Andreassen OA, Anjorin A, Anney R, Anttila V, Arking DE, Asherson P, Azevedo MH, Backlund L, Badner JA, Bailey AJ, Banaschewski T, Barchas JD, Barnes MR, Barrett TB, Bass N, Battaglia A, Bauer M, Bayés M, Bellivier F, Bergen SE, Berrettini W, Betancur C, Bettecken T, Biederman J, Binder EB, Black DW, Blackwood DH, Bloss CS, Boehnke M, Boomsma DI, Breen G, Breuer R, Bruggeman R, Cormican P, Buccola NG, Buitelaar JK, Bunney WE, Buxbaum JD, Byerley WF, Byrne EM, Caesar S, Cahn W, Cantor RM, Casas M, Chakravarti A, Chambert K, Choudhury K, Cichon S, Cloninger CR, Collier DA, Cook EH, Coon H, Cormand B, Corvin A, Coryell WH, Craig DW, Craig IW, Crosbie J, Cuccaro ML, Curtis D, Czamara D, Datta S, Dawson G, Day R, De Geus EJ, Degenhardt F, Djurovic S, Donohoe GJ, Doyle AE, Duan J, Dudbridge F, Duketis E, Ebstein RP, Edenberg HJ, Elia J, Ennis S, Etain B, Fanous A, Farmer AE, Ferrier IN, Flickinger M, Fombonne E, Foroud T, Frank J, Franke B, Fraser C, Freedman R, Freimer NB, Freitag CM, Friedl M, Frisén L, Gallagher L, Gejman PV, Georgieva L, Gershon ES, Geschwind DH, Giegling I, Gill M, Gordon SD, Gordon-Smith K, Green EK, Greenwood TA, Grice DE, Gross M, Grozeva D, Guan W, Gurling H, De Haan L, Haines JL, Hakonarson H, Hallmayer J, Hamilton SP, Hamshere ML, Hansen TF, Hartmann AM, Hautzinger M, Heath AC, Henders AK, Herms S, Hickie IB, Hipolito M, Hoefels S, Holmans PA, Holsboer F, Hoogendijk WJ, Hottenga JJ, Hultman CM, Hus V, Ingason A, Ising M, Jamain S, Jones EG, Jones I, Jones L, Tzeng JY, Kähler AK, Kahn RS, Kandaswamy R, Keller MC, Kennedy JL, Kenny E, Kent L, Kim Y, Kirov GK, Klauck SM, Klei L, Knowles JA, Kohli MA, Koller DL, Konte B, Korszun A, Krabbendam L, Krasucki R, Kuntsi J, Kwan P, Landén M, Långström N, Lathrop M, Lawrence J, Lawson WB, Leboyer M, Ledbetter DH, Lee PH, Lencz T, Lesch KP, Levinson DF, Lewis CM, Li J, Lichtenstein P, Lieberman JA, Lin DY, Linszen DH, Liu C, Lohoff FW, Loo SK, Lord C, Lowe JK, Lucae S, MacIntyre DJ, Madden PA, Maestrini E, Magnusson PK, Mahon PB, Maier W, Malhotra AK, Mane SM, Martin CL, Martin NG, Mattheisen M, Matthews K, Mattingsdal M, McCarroll SA, McGhee KA, McGough JJ, McGrath PJ, McGuffin P, McInnis MG, McIntosh A, McKinney R, McLean AW, McMahon FJ, McMahon WM, McQuillin A, Medeiros H, Medland SE, Meier S, Melle I, Meng F, Meyer J, Middeldorp CM, Middleton L, Milanova V, Miranda A, Monaco AP, Montgomery GW, Moran JL, Moreno-De-Luca D, Morken G, Morris DW, Morrow EM, Moskvina V, Muglia P, Mühleisen TW, Muir WJ, Müller-Myhsok B, Murtha M, Myers RM, Myin-Germeys I, Neale MC, Nelson SF, Nievergelt CM, Nikolov I, Nimgaonkar V, Nolen WA, Nöthen MM, Nurnberger JI, Nwulia EA, Nyholt DR, O'Dushlaine C, Oades RD, Olincy A, Oliveira G, Olsen L, Ophoff RA, Osby U, Owen MJ, Palotie A, Parr JR, Paterson AD, Pato CN, Pato MT, Penninx BW, Pergadia ML, Pericak-Vance MA, Pickard BS, Pimm J, Piven J, Posthuma D, Potash JB, Poustka F, Propping P, Puri V, Quested DJ, Quinn EM, Ramos-Quiroga JA, Rasmussen HB, Raychaudhuri S, Rehnström K, Reif A, Ribasés M, Rice JP, Rietschel M, Roeder K, Roeyers H, Rossin L, Rothenberger A, Rouleau G, Ruderfer D, Rujescu D, Sanders AR, Sanders SJ, Santangelo SL, Sergeant JA, Schachar R, Schalling M, Schatzberg AF, Scheftner WA, Schellenberg GD, Scherer SW, Schork NJ, Schulze TG, Schumacher J, Schwarz M, Scolnick E, Scott LJ, Shi J, Shilling PD, Shyn SI, Silverman JM, Slager SL, Smalley SL, Smit JH, Smith EN, Sonuga-Barke EJ, St Clair D, State M, Steffens M, Steinhausen HC, Strauss JS, Strohmaier J, Stroup TS, Sutcliffe JS, Szatmari P, Szelinger S, Thirumalai S, Thompson RC, Todorov AA, Tozzi F, Treutlein J, Uhr M, van den Oord EJ, Van Grootheest G, Van Os J, Vicente AM, Vieland VJ, Vincent JB, Visscher PM, Walsh CA, Wassink TH, Watson SJ, Weissman MM, Werge T, Wienker TF, Wijsman EM, Willemsen G, Williams N, Willsey AJ, Witt SH, Xu W, Young AH, Yu TW, Zammit S, Zandi PP, Zhang P, Zitman FG, Zöllner S, Devlin B, Kelsoe JR, Sklar P, Daly MJ, O'Donovan MC, Craddock N, Sullivan PF, Smoller JW, Kendler KS, Wray NR, Cardiff University-Medical Research Council (MRC), HudsonAlpha Institute for Biotechnology, The Institute of Psychiatry-King‘s College London, Cornell University-Weill Medical College of Cornell University [New York], Stanford University Medical School, Technische Universität Dresden (TUD)-University Hospital Carl Gustav Carus, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, McGill University-Montreal Children's Hospital, Universidade Federal do Rio de Janeiro [Rio de Janeiro] (UFRJ), Stanford University School of Medicine [Stanford], Stanford University [Stanford], Eberhard Karls Universität Tübingen, Friedrich Alexander University [Erlangen-Nürnberg], Università di Bologna [Bologna] (UNIBO), University of Toronto-The Hospital for Sick Children-Department of Molecular Genetics-McLaughlin Centre, Washington University School of Medicine, Ghent University [Belgium] (UGENT), University of Goettingen, CHUM Research Center, Psychiatry and Behavioral Science, Stanford University School of Medicine [CA, USA], Aalborg Psychiatric Hospital, Aarhus University Hospital, Washington University in St Louis, Instituto Nacional de Saude Dr Ricardo Jorge, Oades, Robert D., Guellaen, Georges, Medical Oncology, Epidemiology, Child and Adolescent Psychiatry / Psychology, and Hematology
Subjects: Netherlands Twin Register (NTR), Medizin, Inheritance Patterns, Social Sciences, AUTISM SPECTRUM DISORDERS, nosology, heritability, COMMON SNPS, 0302 clinical medicine, Crohn Disease, SCHIZOPHRENIA, Child, Psychiatric genetics, Genetics & Heredity, MAJOR DEPRESSIVE DISORDER, RISK, 0303 health sciences, ATTENTION-DEFICIT/HYPERACTIVITY DISORDER, 120 000 Neuronal Coherence, Mental Disorders, Variants, BIPOLAR DISORDER, ASSOCIATION, Genomic disorders and inherited multi-system disorders [DCN PAC - Perception action and control IGMD 3], Psychiatric Disorders, CROHNS-DISEASE, 3. Good health, Schizophrenia, genetic association study, Medical genetics, Major depressive disorder, SNPs, Adult, medicine.medical_specialty, genetic etiology, medical genetics, DEFICIT HYPERACTIVITY DISORDER, Biology, Polymorphism, Single Nucleotide, behavioral disciplines and activities, Article, Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory [IGMD 3], Heritability, Genetic Heterogeneity, 03 medical and health sciences, Prevalence of mental disorders, mental disorders, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetics, medicine, ddc:61, Humans, Attention deficit hyperactivity disorder, Genetic Predisposition to Disease, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, DCN PAC - Perception action and control NCEBP 9 - Mental health, ddc:610, Medizinische Fakultät » Universitätsklinikum Essen » LVR-Klinikum Essen » Klinik für Psychiatrie, Psychosomatik und Psychotherapie des Kindes- und Jugendalters, Bipolar disorder, Psychiatry, 030304 developmental biology, Depressive Disorder, Major, Genome, Human, Genetic heterogeneity, medicine.disease, schizophrenia, Attention Deficit Disorder with Hyperactivity, Child Development Disorders, Pervasive, Perturbações do Desenvolvimento Infantil e Saúde Mental, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: AM Vicente - Cross-Disorder Group of the Psychiatric Genomics Consortium Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.
Published: 2013
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22. Genome-wide association analysis of composite sleep health scores in 413,904 individuals.

Author: Goodman MO, Faquih T, Paz V, Nagarajan P, Lane JM, Spitzer B, Maher M, Chung J, Cade BE, Purcell SM, Zhu X, Noordam R, Phillips AJK, Kyle SD, Spiegelhalder K, Weedon MN, Lawlor DA, Rotter JI, Taylor KD, Isasi CR, Sofer T, Dashti HS, Rutter MK, Redline S, Saxena R, and Wang H
Subjects: Humans, Male, Female, Polymorphism, Single Nucleotide, Middle Aged, Adult, Genome-Wide Association Study, Sleep genetics
Abstract: Recent genome-wide association studies (GWASs) of several individual sleep traits have identified hundreds of genetic loci, suggesting diverse mechanisms. Moreover, sleep traits are moderately correlated, so together may provide a more complete picture of sleep health, while illuminating distinct domains. Here we construct novel sleep health scores (SHSs) incorporating five core self-report measures: sleep duration, insomnia symptoms, chronotype, snoring, and daytime sleepiness, using additive (SHS-ADD) and five principal components-based (SHS-PCs) approaches. GWASs of these six SHSs identify 28 significant novel loci adjusting for multiple testing on six traits (p < 8.3e-9), along with 341 previously reported loci (p < 5e-08). The heritability of the first three SHS-PCs equals or exceeds that of SHS-ADD (SNP-h 2 = 0.094), while revealing sleep-domain-specific genetic discoveries. Significant loci enrich in multiple brain tissues and in metabolic and neuronal pathways. Post-GWAS analyses uncover novel genetic mechanisms underlying sleep health and reveal connections (including potential causal links) to behavioral, psychological, and cardiometabolic traits., Competing Interests: Competing interests: The authors declare the following competing interests: A.J.K.P. has received research funding from Versalux and Delos, and he is co-founder and co-director of Circadian Health Innovations PTY LTD. S.R. received consulting fees from Jazz Pharma, Eli Lilly, and ApniMed Inc. Martin Rutter has received consulting fees from Eli Lilly. All other authors declare no competing interests., (© 2025. The Author(s).)
Published: 2025
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23. Sleep macro-architecture and dementia risk in adults: Meta-analysis of 5 cohorts from the Sleep and Dementia Consortium.

Author: Yiallourou S, Baril AA, Wiedner C, Misialek JR, Kline CE, Harrison S, Cannon E, Yang Q, Bernal R, Bisson A, Himali D, Cavuoto M, Weihs A, Beiser A, Gottesman RF, Leng Y, Lopez O, Lutsey PL, Purcell SM, Redline S, Seshadri S, Stone KL, Yaffe K, Ancoli-Israel S, Xiao Q, Vaou EO, Himali JJ, and Pase MP
Abstract: Study Objectives: Poor sleep may play a role in the risk of dementia. However, few studies have investigated the association between polysomnography (PSG)-derived sleep architecture and dementia incidence. We examined the relationship between sleep macro-architecture and dementia incidence across five US-based cohort studies from the Sleep and Dementia Consortium (SDC)., Methods: Percent of time spent in stages of sleep (N1, N2, N3, REM sleep), wake after sleep onset and sleep maintenance efficiency were derived from a single night home-based PSG. Dementia was ascertained in each cohort using its cohort-specific criteria. Each cohort performed Cox proportional hazard regressions for each sleep exposure and incident dementia, adjusting for age, sex, body mass index, anti-depressant use, sedative use, and APOE e4 status. Results were then pooled in random effects meta-analyses., Results: The pooled sample comprised 4,657 participants (30% women) aged ≥60 years (mean age was 74 years at sleep assessment). There were 998 (21.4%) dementia cases (median follow-up time of 5 to 19 years). Pooled effects of the five cohorts showed no association between sleep architecture and incident dementia. When meta-analyses were restricted to the three cohorts which had dementia case ascertainment based on DSM-IV/V criteria (n=2,374), higher N3% was marginally associated with an increased risk of dementia (HR: 1.06; 95%CI: 1.00-1.12, per percent increase N3, p=0.050)., Conclusions: There were no consistent associations between sleep macro-architecture measured and the risk of incident dementia. Implementing more nuanced sleep metrics remains an important next step for uncovering more about sleep-dementia associations.
Published: 2024
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24. Gene-Excessive Sleepiness Interactions Suggest Treatment Targets for Obstructive Sleep Apnea Subtype.

Author: Nagarajan P, Kurniansyah N, Lee J, Gharib SA, Xu Y, Zhang Y, Spitzer B, Faquih T, Zhou H, Boerwinkle E, Chen H, Gottlieb DJ, Guo X, Heard-Costa NL, Hidalgo BA, Levy D, Liu PY, Mei H, Montalvan R, Mukherjee S, North KE, O'Conner GT, Palmer LJ, Patel SR, Psaty BM, Purcell SM, Raffield LM, Rich SS, Rotter JI, Saxena R, Smith AV, Stone KL, Zhu X, Cade BE, Sofer T, Redline S, and Wang H
Abstract: Obstructive sleep apnea (OSA) is a multifactorial sleep disorder characterized by a strong genetic basis. Excessive daytime sleepiness (EDS) is a symptom that is reported by a subset of OSA patients, persisting even after treatment with continuous positive airway pressure (CPAP). It is recognized as a clinical subtype underlying OSA carrying alarming heightened cardiovascular risk. Thus, conceptualizing EDS as an exposure variable, we sought to investigate EDS's influence on genetic variation linked to apnea-hypopnea index (AHI), a diagnostic measure of OSA severity. This study serves as the first large-scale genome-wide gene x environment interaction analysis for AHI, investigating the interplay between its genetic markers and EDS across and within specific sex. Our work pools together whole genome sequencing data from seven cohorts, enabling a diverse dataset (four population backgrounds) of over 11,500 samples. Among the total 16 discovered genetic targets with interaction evidence with EDS, eight are previously unreported for OSA, including CCDC3 , MARCHF1 , and MED31 identified in all sexes; TMEM26 , CPSF4L , and PI4K2B identified in males; and RAP1GAP and YY1 identified in females. We discuss connections to insulin resistance, thiamine deficiency, and resveratrol use that may be worthy of therapeutic consideration for excessively sleepy OSA patients., Competing Interests: Competing Interests: LMR is a consultant for the TOPMed Administrative Coordinating Center (through Westat).
Published: 2024
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25. A spectrum of altered non-rapid eye movement sleep in schizophrenia.

Author: Kozhemiako N, Jiang C, Sun Y, Guo Z, Chapman S, Gai G, Wang Z, Zhou L, Li S, Law RG, Wang LA, Mylonas D, Shen L, Murphy M, Qin S, Zhu W, Zhou Z, Stickgold R, Huang H, Tan S, Manoach DS, Wang J, Hall MH, Pan JQ, and Purcell SM
Abstract: Multiple facets of sleep neurophysiology, including electroencephalography (EEG) metrics such as non-rapid eye movement (NREM) spindles and slow oscillations, are altered in individuals with schizophrenia (SCZ). However, beyond group-level analyses, the extent to which NREM deficits vary among patients is unclear, as are their relationships to other sources of heterogeneity including clinical factors, ageing, cognitive profiles and medication regimens. Using newly collected high-density sleep EEG data on 103 individuals with SCZ and 68 controls, we first sought to replicate our previously reported group-level differences between patients and controls (original N=130) during N2 stage. Then in the combined sample (N=301 including 175 patients), we characterized patient-to-patient variability. We replicated all group-level mean differences and confirmed the high accuracy of our predictive model (AUC=0.93 for diagnosis). Compared to controls, patients showed significantly increased between-individual variability across many (26%) sleep metrics. Although multiple clinical and cognitive factors were associated with NREM metrics, collectively they did not account for much of the general increase in patient-to-patient variability. Medication regimen was a greater contributor to variability. Some sleep metrics including fast spindle density showed exaggerated age-related effects in SCZ, and patients exhibited older predicted biological ages based on the sleep EEG; further, among patients, certain medications exacerbated these effects, in particular olanzapine. Collectively, our results point to a spectrum of N2 sleep deficits among SCZ patients that can be measured objectively and at scale, with relevance to both the etiological heterogeneity of SCZ as well as potential iatrogenic effects of antipsychotic medication., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society.)
Published: 2024
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26. Electroencephalographic Microstates During Sleep and Wake in Schizophrenia.

Author: Murphy M, Jiang C, Wang LA, Kozhemiako N, Wang Y, Wang J, Pan JQ, and Purcell SM
Abstract: Background: Aberrant functional connectivity is a hallmark of schizophrenia. The precise nature and mechanism of dysconnectivity in schizophrenia remains unclear, but evidence suggests that dysconnectivity is different in wake versus sleep. Microstate analysis uses electroencephalography (EEG) to investigate large-scale patterns of coordinated brain activity by clustering EEG data into a small set of recurring spatial patterns, or microstates. We hypothesized that this technique would allow us to probe connectivity between brain networks at a fine temporal resolution and uncover previously unknown sleep-specific dysconnectivity., Methods: We studied microstates during sleep in patients with schizophrenia by analyzing high-density EEG sleep data from 114 patients with schizophrenia and 79 control participants. We used a polarity-insensitive k -means analysis to extract a set of 6 microstate topographies., Results: These 6 states included 4 widely reported canonical microstates. In patients and control participants, falling asleep was characterized by a shift from microstates A, B, and C to microstates D, E, and F. Microstate F was decreased in patients during wake, and microstate E was decreased in patients during sleep. The complexity of microstate transitions was greater in patients than control participants during wake, but this reversed during sleep., Conclusions: Our findings reveal behavioral state-dependent patterns of cortical dysconnectivity in schizophrenia. Furthermore, these findings are largely unrelated to previous sleep-related EEG markers of schizophrenia such as decreased sleep spindles. Therefore, these findings are driven by previously undescribed sleep-related pathology in schizophrenia., (© 2024 The Authors.)
Published: 2024
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27. Study Protocol: Global Research Initiative on the Neurophysiology of Schizophrenia (GRINS) project.

Author: Wang J, Jiang C, Guo Z, Chapman S, Kozhemiako N, Mylonas D, Su Y, Zhou L, Shen L, Qin S, Murphy M, Tan S, Manoach DS, Stickgold R, Huang H, Zhou Z, Purcell SM, Hall M, Hyman SE, and Pan JQ
Subjects: Adult, Female, Humans, Male, Biomarkers, Cohort Studies, Neurophysiology methods, Research Design, Sleep physiology, Cross-Sectional Studies, Middle Aged, Aged, Electroencephalography methods, Schizophrenia physiopathology, Schizophrenia diagnosis
Abstract: Background: Objective and quantifiable markers are crucial for developing novel therapeutics for mental disorders by 1) stratifying clinically similar patients with different underlying neurobiological deficits and 2) objectively tracking disease trajectory and treatment response. Schizophrenia is often confounded with other psychiatric disorders, especially bipolar disorder, if based on cross-sectional symptoms. Awake and sleep EEG have shown promise in identifying neurophysiological differences as biomarkers for schizophrenia. However, most previous studies, while useful, were conducted in European and American populations, had small sample sizes, and utilized varying analytic methods, limiting comprehensive analyses or generalizability to diverse human populations. Furthermore, the extent to which wake and sleep neurophysiology metrics correlate with each other and with symptom severity or cognitive impairment remains unresolved. Moreover, how these neurophysiological markers compare across psychiatric conditions is not well characterized. The utility of biomarkers in clinical trials and practice would be significantly advanced by well-powered transdiagnostic studies. The Global Research Initiative on the Neurophysiology of Schizophrenia (GRINS) project aims to address these questions through a large, multi-center cohort study involving East Asian populations. To promote transparency and reproducibility, we describe the protocol for the GRINS project., Methods: The research procedure consists of an initial screening interview followed by three subsequent sessions: an introductory interview, an evaluation visit, and an overnight neurophysiological recording session. Data from multiple domains, including demographic and clinical characteristics, behavioral performance (cognitive tasks, motor sequence tasks), and neurophysiological metrics (both awake and sleep electroencephalography), are collected by research groups specialized in each domain., Conclusion: Pilot results from the GRINS project demonstrate the feasibility of this study protocol and highlight the importance of such research, as well as its potential to study a broader range of patients with psychiatric conditions. Through GRINS, we are generating a valuable dataset across multiple domains to identify neurophysiological markers of schizophrenia individually and in combination. By applying this protocol to related mental disorders often confounded with each other, we can gather information that offers insight into the neurophysiological characteristics and underlying mechanisms of these severe conditions, informing objective diagnosis, stratification for clinical research, and ultimately, the development of better-targeted treatment matching in the clinic., (© 2024. The Author(s).)
Published: 2024
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28. MIR137 polygenic risk for schizophrenia and ephrin-regulated pathway: Role in lateral ventricles and corpus callosum volume.

Author: Blokland GAM, Maleki N, Jovicich J, Mesholam-Gately RI, DeLisi LE, Turner JA, Shenton ME, Voineskos AN, Kahn RS, Roffman JL, Holt DJ, Ehrlich S, Kikinis Z, Dazzan P, Murray RM, Lee J, Sim K, Lam M, de Zwarte SMC, Walton E, Kelly S, Picchioni MM, Bramon E, Makris N, David AS, Mondelli V, Reinders AATS, Oykhman E, Morris DW, Gill M, Corvin AP, Cahn W, Ho N, Liu J, Gollub RL, Manoach DS, Calhoun VD, Sponheim SR, Buka SL, Cherkerzian S, Thermenos HW, Dickie EW, Ciufolini S, Reis Marques T, Crossley NA, Purcell SM, Smoller JW, van Haren NEM, Toulopoulou T, Donohoe G, Goldstein JM, Keshavan MS, Petryshen TL, and Del Re EC
Abstract: Background/Objective. Enlarged lateral ventricle (LV) volume and decreased volume in the corpus callosum (CC) are hallmarks of schizophrenia (SZ). We previously showed an inverse correlation between LV and CC volumes in SZ, with global functioning decreasing with increased LV volume. This study investigates the relationship between LV volume, CC abnormalities, and the microRNA MIR137 and its regulated genes in SZ, because of MIR137's essential role in neurodevelopment. Methods . Participants were 1224 SZ probands and 1466 unaffected controls from the GENUS Consortium. Brain MRI scans, genotype, and clinical data were harmonized across cohorts and employed in the analyses. Results. Increased LV volumes and decreased CC central, mid-anterior, and mid-posterior volumes were observed in SZ probands. The MIR137-regulated ephrin pathway was significantly associated with CC:LV ratio, explaining a significant proportion (3.42 %) of CC:LV variance, and more than for LV and CC separately. Other pathways explained variance in either CC or LV, but not both. CC:LV ratio was also positively correlated with Global Assessment of Functioning, supporting previous subsample findings. SNP-based heritability estimates were higher for CC central:LV ratio (0.79) compared to CC or LV separately. Discussion. Our results indicate that the CC:LV ratio is highly heritable, influenced in part by variation in the MIR137-regulated ephrin pathway. Findings suggest that the CC:LV ratio may be a risk indicator in SZ that correlates with global functioning., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The author is an Editorial Board Member/Editor-in-Chief/Associate Editor/Guest Editor for International Journal of Clinical and Health Psychology and was not involved in the editorial review or the decision to publish this article., (© 2024 The Author(s).)
Published: 2024
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29. A Potential Source of Bias in Group-Level EEG Microstate Analysis.

Author: Murphy M, Wang J, Jiang C, Wang LA, Kozhemiako N, Wang Y, Pan JQ, and Purcell SM
Subjects: Humans, Healthy Volunteers, Probability, Upper Extremity, Brain, Electroencephalography methods
Abstract: Microstate analysis is a promising technique for analyzing high-density electroencephalographic data, but there are multiple questions about methodological best practices. Between and within individuals, microstates can differ both in terms of characteristic topographies and temporal dynamics, which leads to analytic challenges as the measurement of microstate dynamics is dependent on assumptions about their topographies. Here we focus on the analysis of group differences, using simulations seeded on real data from healthy control subjects to compare approaches that derive separate sets of maps within subgroups versus a single set of maps applied uniformly to the entire dataset. In the absence of true group differences in either microstate maps or temporal metrics, we found that using separate subgroup maps resulted in substantially inflated type I error rates. On the other hand, when groups truly differed in their microstate maps, analyses based on a single set of maps confounded topographic effects with differences in other derived metrics. We propose an approach to alleviate both classes of bias, based on a paired analysis of all subgroup maps. We illustrate the qualitative and quantitative impact of these issues in real data by comparing waking versus non-rapid eye movement sleep microstates. Overall, our results suggest that even subtle chance differences in microstate topography can have profound effects on derived microstate metrics and that future studies using microstate analysis should take steps to mitigate this large source of error., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Published: 2024
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30. Genome-wide association analysis of composite sleep health scores in 413,904 individuals.

Author: Goodman MO, Faquih T, Paz V, Nagarajan P, Lane JM, Spitzer B, Maher M, Chung J, Cade BE, Purcell SM, Zhu X, Noordam R, Phillips AJK, Kyle SD, Spiegelhalder K, Weedon MN, Lawlor DA, Rotter JI, Taylor KD, Isasi CR, Sofer T, Dashti HS, Rutter MK, Redline S, Saxena R, and Wang H
Abstract: Recent genome-wide association studies (GWASs) of several individual sleep traits have identified hundreds of genetic loci, suggesting diverse mechanisms. Moreover, sleep traits are moderately correlated, and together may provide a more complete picture of sleep health, while also illuminating distinct domains. Here we construct novel sleep health scores (SHSs) incorporating five core self-report measures: sleep duration, insomnia symptoms, chronotype, snoring, and daytime sleepiness, using additive (SHS-ADD) and five principal components-based (SHS-PCs) approaches. GWASs of these six SHSs identify 28 significant novel loci adjusting for multiple testing on six traits (p<8.3e-9), along with 341 previously reported loci (p<5e-08). The heritability of the first three SHS-PCs equals or exceeds that of SHS-ADD (SNP-h 2 =0.094), while revealing sleep-domain-specific genetic discoveries. Significant loci enrich in multiple brain tissues and in metabolic and neuronal pathways. Post GWAS analyses uncover novel genetic mechanisms underlying sleep health and reveal connections to behavioral, psychological, and cardiometabolic traits.
Published: 2024
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31. Objectively regular sleep patterns and mortality in a prospective cohort: The Multi-Ethnic Study of Atherosclerosis.

Author: Chung J, Goodman MO, Huang T, Castro-Diehl C, Chen JT, Sofer T, Bertisch SM, Purcell SM, and Redline S
Subjects: Adult, Humans, Prospective Studies, Polysomnography, Sleep Deprivation, Actigraphy, Sleep, Atherosclerosis
Abstract: Irregular sleep and non-optimal sleep duration separately have been shown to be associated with increased disease and mortality risk. We used data from the prospective cohort Multi-Ethnic Study of Atherosclerosis sleep study (2010-2013) to investigate: do aging adults whose sleep is objectively high in regularity in timing and duration, and of sufficient duration tend to have increased survival compared with those whose sleep is lower in regularity and duration, in a diverse US sample? At baseline, sleep was measured by 7-day wrist actigraphy, concurrent with at-home polysomnography and questionnaires. Objective metrics of sleep regularity and duration from actigraphy were used for statistical clustering using sparse k-means clustering. Two sleep patterns were identified: "regular-optimal" (average duration: 7.0 ± 1.0 hr obtained regularly) and "irregular-insufficient" (duration: 5.8 ± 1.4 hr obtained with twice the irregularity). Using proportional hazard models with multivariate adjustment, we estimated all-cause mortality hazard ratios. Among 1759 participants followed for a median of 7.0 years (Q1-Q3, 6.4-7.4 years), 176 deaths were recorded. The "regular-optimal" group had a 39% lower mortality hazard than did the "irregular-insufficient" sleep group (hazard ratio [95% confidence interval]: 0.61 [0.45, 0.83]) after adjusting for socio-demographics, lifestyle, medical comorbidities and sleep disorders. In conclusion, a "regular-optimal" sleep pattern was significantly associated with a lower hazard of all-cause mortality. The regular-optimal phenotype maps behaviourally to regular bed and wake times, suggesting sleep benefits of adherence to recommended healthy sleep practices, with further potential benefits for longevity., (© 2023 European Sleep Research Society.)
Published: 2024
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32. Mapping neurodevelopment with sleep macro- and micro-architecture across multiple pediatric populations.

Author: Kozhemiako N, Buckley AW, Chervin RD, Redline S, and Purcell SM
Subjects: Adolescent, Child, Humans, Brain, Electroencephalography, Polysomnography, Child, Preschool, Clinical Trials as Topic, Sleep, Snoring
Abstract: Profiles of sleep duration and timing and corresponding electroencephalographic activity reflect brain changes that support cognitive and behavioral maturation and may provide practical markers for tracking typical and atypical neurodevelopment. To build and evaluate a sleep-based, quantitative metric of brain maturation, we used whole-night polysomnography data, initially from two large National Sleep Research Resource samples, spanning childhood and adolescence (total N = 4,013, aged 2.5 to 17.5 years): the Childhood Adenotonsillectomy Trial (CHAT), a research study of children with snoring without neurodevelopmental delay, and Nationwide Children's Hospital (NCH) Sleep Databank, a pediatric sleep clinic cohort. Among children without neurodevelopmental disorders (NDD), sleep metrics derived from the electroencephalogram (EEG) displayed robust age-related changes consistently across datasets. During non-rapid eye movement (NREM) sleep, spindles and slow oscillations further exhibited characteristic developmental patterns, with respect to their rate of occurrence, temporal coupling and morphology. Based on these metrics in NCH, we constructed a model to predict an individual's chronological age. The model performed with high accuracy (r = 0.93 in the held-out NCH sample and r = 0.85 in a second independent replication sample - the Pediatric Adenotonsillectomy Trial for Snoring (PATS)). EEG-based age predictions reflected clinically meaningful neurodevelopmental differences; for example, children with NDD showed greater variability in predicted age, and children with Down syndrome or intellectual disability had significantly younger brain age predictions (respectively, 2.1 and 0.8 years less than their chronological age) compared to age-matched non-NDD children. Overall, our results indicate that sleep architectureoffers a sensitive window for characterizing brain maturation, suggesting the potential for scalable, objective sleep-based biomarkers to measure neurodevelopment., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Chervin reports the following financial and non-financial potentially competing interests: consultant (through contract with Michigan Medicine) for Eli Lilly & Company; editor and author, UpToDate; officer and board member for International Pediatric Sleep Association; member, advisory board for a non-profit organization, The Pajama Program. Other authors report no conflict of interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Published: 2024
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33. A spectrum of altered non-rapid eye movement sleep in schizophrenia.

Author: Kozhemiako N, Jiang C, Sun Y, Guo Z, Chapman S, Gai G, Wang Z, Zhou L, Li S, Law RG, Wang LA, Mylonas D, Shen L, Murphy M, Qin S, Zhu W, Zhou Z, Stickgold R, Huang H, Tan S, Manoach DS, Wang J, Hall MH, Pan JQ, and Purcell SM
Abstract: Background: Multiple facets of sleep neurophysiology, including electroencephalography (EEG) metrics such as non-rapid eye movement (NREM) spindles and slow oscillations (SO), are altered in individuals with schizophrenia (SCZ). However, beyond group-level analyses which treat all patients as a unitary set, the extent to which NREM deficits vary among patients is unclear, as are their relationships to other sources of heterogeneity including clinical factors, illness duration and ageing, cognitive profiles and medication regimens. Using newly collected high density sleep EEG data on 103 individuals with SCZ and 68 controls, we first sought to replicate our previously reported (Kozhemiako et. al, 2022) group-level mean differences between patients and controls (original N =130). Then in the combined sample ( N =301 including 175 patients), we characterized patient-to-patient variability in NREM neurophysiology., Results: We replicated all group-level mean differences and confirmed the high accuracy of our predictive model (Area Under the ROC Curve, AUC = 0.93 for diagnosis). Compared to controls, patients showed significantly increased between-individual variability across many (26%) sleep metrics, with patterns only partially recapitulating those for group-level mean differences. Although multiple clinical and cognitive factors were associated with NREM metrics including spindle density, collectively they did not account for much of the general increase in patient-to-patient variability. Medication regimen was a greater (albeit still partial) contributor to variability, although original group mean differences persisted after controlling for medications. Some sleep metrics including fast spindle density showed exaggerated age-related effects in SCZ, and patients exhibited older predicted biological ages based on an independent model of ageing and the sleep EEG., Conclusion: We demonstrated robust and replicable alterations in sleep neurophysiology in individuals with SCZ and highlighted distinct patterns of effects contrasting between-group means versus within-group variances. We further documented and controlled for a major effect of medication use, and pointed to greater age-related change in NREM sleep in patients. That increased NREM heterogeneity was not explained by standard clinical or cognitive patient assessments suggests the sleep EEG provides novel, nonredundant information to support the goals of personalized medicine. Collectively, our results point to a spectrum of NREM sleep deficits among SCZ patients that can be measured objectively and at scale, and that may offer a unique window on the etiological and genetic diversity that underlies SCZ risk, treatment response and prognosis.
Published: 2023
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34. Causal Association Between Subtypes of Excessive Daytime Sleepiness and Risk of Cardiovascular Diseases.

Author: Goodman MO, Dashti HS, Lane JM, Windred DP, Burns A, Jones SE, Sofer T, Purcell SM, Zhu X, Ollila HM, Kyle SD, Spiegelhalder K, Peker Y, Huang T, Cain SW, Phillips AJK, Saxena R, Rutter MK, Redline S, and Wang H
Subjects: Humans, Sleep, Cardiovascular Diseases diagnosis, Cardiovascular Diseases epidemiology, Cardiovascular Diseases genetics, Disorders of Excessive Somnolence diagnosis, Disorders of Excessive Somnolence epidemiology, Disorders of Excessive Somnolence genetics, Myocardial Infarction epidemiology, Myocardial Infarction genetics, Myocardial Infarction complications, Stroke diagnosis, Stroke epidemiology, Stroke genetics
Abstract: Background: Excessive daytime sleepiness (EDS), experienced in 10% to 20% of the population, has been associated with cardiovascular disease and death. However, the condition is heterogeneous and is prevalent in individuals having short and long sleep duration. We sought to clarify the relationship between sleep duration subtypes of EDS with cardiovascular outcomes, accounting for these subtypes., Methods and Results: We defined 3 sleep duration subtypes of excessive daytime sleepiness: normal (6-9 hours), short (<6 hours), and long (>9 hours), and compared these with a nonsleepy, normal-sleep-duration reference group. We analyzed their associations with incident myocardial infarction (MI) and stroke using medical records of 355 901 UK Biobank participants and performed 2-sample Mendelian randomization for each outcome. Compared with healthy sleep, long-sleep EDS was associated with an 83% increased rate of MI (hazard ratio, 1.83 [95% CI, 1.21-2.77]) during 8.2-year median follow-up, adjusting for multiple health and sociodemographic factors. Mendelian randomization analysis provided supporting evidence of a causal role for a genetic long-sleep EDS subtype in MI (inverse-variance weighted β=1.995, P =0.001). In contrast, we did not find evidence that other subtypes of EDS were associated with incident MI or any associations with stroke ( P >0.05)., Conclusions: Our study suggests the previous evidence linking EDS with increased cardiovascular disease risk may be primarily driven by the effect of its long-sleep subtype on higher risk of MI. Underlying mechanisms remain to be investigated but may involve sleep irregularity and circadian disruption, suggesting a need for novel interventions in this population.
Published: 2023
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35. Superthermal Al Atoms as a Reactive-Atom Probe of Fluorinated Surfaces.

Author: Lane PD, Gstir T, Purcell SM, Swierczewski M, Elstone NS, Bruce DW, Slattery JM, Costen ML, and McKendrick KG
Abstract: We demonstrate a proof-of-concept of a new analytical technique to measure relative F atom exposure at the surfaces of fluorinated materials. The method is based on reactive-atom scattering (RAS) of Al atoms, produced by pulsed laser ablation of solid Al at 532 nm. The properties of the incident ground-state Al were characterized by laser-induced fluorescence (LIF); at typical ablation fluences, the speed distribution is approximately Maxwellian at ∼45000 K, with a most-probable kinetic energy of 187 kJ mol -1 and a mean of 560 kJ mol -1 When these Al atoms impact the surfaces of perfluorinated solids (poly(tetrafluorethylene), PTFE) or liquids (perfluoropolyether, PFPE), gas-phase AlF products are clearly detectable by LIF on the AlF A-X band. Quantitative AlF yields were compared for a small representative set of a widely studied family of ionic liquids based on the common 1-alkyl-3-methylimidazolium ([C n mim] + ) cation. Yields of (1.9 ± 0.2):1 were found from [C 2 mim][Tf 2 N] and [C 8 mim][Tf 2 N], containing the common fluorinated bis(trifluoromethylsulfonyl)imide anion ([Tf 2 N] - ). This is in quantitative agreement with previous independent low-energy ion scattering (LEIS) measurements and consistent with other independent results indicating that the longer cationic alkyl chains cover a larger fraction of the liquid surface and hence reduce anion exposure. The expected null result was obtained for the ionic liquid [C 2 mim][EtSO 4 ] which contains no fluorine. These results open the way for further characterization and the potential application of this new variant of the RAS-LIF method.
Published: 2023
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36. Sleep Architecture, Obstructive Sleep Apnea, and Cognitive Function in Adults.

Author: Pase MP, Harrison S, Misialek JR, Kline CE, Cavuoto M, Baril AA, Yiallourou S, Bisson A, Himali D, Leng Y, Yang Q, Seshadri S, Beiser A, Gottesman RF, Redline S, Lopez O, Lutsey PL, Yaffe K, Stone KL, Purcell SM, and Himali JJ
Subjects: Male, Female, Humans, Adult, Middle Aged, Aged, Aged, 80 and over, Cognition, Sleep, Osteoporotic Fractures, Sleep Apnea, Obstructive complications, Sleep Apnea, Obstructive epidemiology, Dementia epidemiology, Dementia complications
Abstract: Importance: Good sleep is essential for health, yet associations between sleep and dementia risk remain incompletely understood. The Sleep and Dementia Consortium was established to study associations between polysomnography (PSG)-derived sleep and the risk of dementia and related cognitive and brain magnetic resonance imaging endophenotypes., Objective: To investigate association of sleep architecture and obstructive sleep apnea (OSA) with cognitive function in the Sleep and Dementia Consortium., Design, Setting, and Participants: The Sleep and Dementia Consortium curated data from 5 population-based cohorts across the US with methodologically consistent, overnight, home-based type II PSG and neuropsychological assessments over 5 years of follow-up: the Atherosclerosis Risk in Communities study, Cardiovascular Health Study, Framingham Heart Study (FHS), Osteoporotic Fractures in Men Study, and Study of Osteoporotic Fractures. Sleep metrics were harmonized centrally and then distributed to participating cohorts for cohort-specific analysis using linear regression; study-level estimates were pooled in random effects meta-analyses. Results were adjusted for demographic variables, the time between PSG and neuropsychological assessment (0-5 years), body mass index, antidepressant use, and sedative use. There were 5946 participants included in the pooled analyses without stroke or dementia. Data were analyzed from March 2020 to June 2023., Exposures: Measures of sleep architecture and OSA derived from in-home PSG., Main Outcomes and Measures: The main outcomes were global cognitive composite z scores derived from principal component analysis, with cognitive domains investigated as secondary outcomes. Higher scores indicated better performance., Results: Across cohorts, 5946 adults (1875 females [31.5%]; mean age range, 58-89 years) were included. The median (IQR) wake after sleep onset time ranged from 44 (27-73) to 101 (66-147) minutes, and the prevalence of moderate to severe OSA ranged from 16.9% to 28.9%. Across cohorts, higher sleep maintenance efficiency (pooled β per 1% increase, 0.08; 95% CI, 0.03 to 0.14; P < .01) and lower wake after sleep onset (pooled β per 1-min increase, -0.07; 95% CI, -0.13 to -0.01 per 1-min increase; P = .02) were associated with better global cognition. Mild to severe OSA (apnea-hypopnea index [AHI] ≥5) was associated with poorer global cognition (pooled β, -0.06; 95% CI, -0.11 to -0.01; P = .01) vs AHI less than 5; comparable results were found for moderate to severe OSA (pooled β, -0.06; 95% CI, -0.11 to -0.01; P = .02) vs AHI less than 5. Differences in sleep stages were not associated with cognition., Conclusions and Relevance: This study found that better sleep consolidation and the absence of OSA were associated with better global cognition over 5 years of follow-up. These findings suggest that the role of interventions to improve sleep for maintaining cognitive function requires investigation.
Published: 2023
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37. AI-Driven sleep staging from actigraphy and heart rate.

Author: Song TA, Chowdhury SR, Malekzadeh M, Harrison S, Hoge TB, Redline S, Stone KL, Saxena R, Purcell SM, and Dutta J
Subjects: Male, Humans, Heart Rate physiology, Sleep physiology, Sleep Stages physiology, Time Factors, Reproducibility of Results, Actigraphy, Artificial Intelligence
Abstract: Sleep is an important indicator of a person's health, and its accurate and cost-effective quantification is of great value in healthcare. The gold standard for sleep assessment and the clinical diagnosis of sleep disorders is polysomnography (PSG). However, PSG requires an overnight clinic visit and trained technicians to score the obtained multimodality data. Wrist-worn consumer devices, such as smartwatches, are a promising alternative to PSG because of their small form factor, continuous monitoring capability, and popularity. Unlike PSG, however, wearables-derived data are noisier and far less information-rich because of the fewer number of modalities and less accurate measurements due to their small form factor. Given these challenges, most consumer devices perform two-stage (i.e., sleep-wake) classification, which is inadequate for deep insights into a person's sleep health. The challenging multi-class (three, four, or five-class) staging of sleep using data from wrist-worn wearables remains unresolved. The difference in the data quality between consumer-grade wearables and lab-grade clinical equipment is the motivation behind this study. In this paper, we present an artificial intelligence (AI) technique termed sequence-to-sequence LSTM for automated mobile sleep staging (SLAMSS), which can perform three-class (wake, NREM, REM) and four-class (wake, light, deep, REM) sleep classification from activity (i.e., wrist-accelerometry-derived locomotion) and two coarse heart rate measures-both of which can be reliably obtained from a consumer-grade wrist-wearable device. Our method relies on raw time-series datasets and obviates the need for manual feature selection. We validated our model using actigraphy and coarse heart rate data from two independent study populations: the Multi-Ethnic Study of Atherosclerosis (MESA; N = 808) cohort and the Osteoporotic Fractures in Men (MrOS; N = 817) cohort. SLAMSS achieves an overall accuracy of 79%, weighted F1 score of 0.80, 77% sensitivity, and 89% specificity for three-class sleep staging and an overall accuracy of 70-72%, weighted F1 score of 0.72-0.73, 64-66% sensitivity, and 89-90% specificity for four-class sleep staging in the MESA cohort. It yielded an overall accuracy of 77%, weighted F1 score of 0.77, 74% sensitivity, and 88% specificity for three-class sleep staging and an overall accuracy of 68-69%, weighted F1 score of 0.68-0.69, 60-63% sensitivity, and 88-89% specificity for four-class sleep staging in the MrOS cohort. These results were achieved with feature-poor inputs with a low temporal resolution. In addition, we extended our three-class staging model to an unrelated Apple Watch dataset. Importantly, SLAMSS predicts the duration of each sleep stage with high accuracy. This is especially significant for four-class sleep staging, where deep sleep is severely underrepresented. We show that, by appropriately choosing the loss function to address the inherent class imbalance, our method can accurately estimate deep sleep time (SLAMSS/MESA: 0.61±0.69 hours, PSG/MESA ground truth: 0.60±0.60 hours; SLAMSS/MrOS: 0.53±0.66 hours, PSG/MrOS ground truth: 0.55±0.57 hours;). Deep sleep quality and quantity are vital metrics and early indicators for a number of diseases. Our method, which enables accurate deep sleep estimation from wearables-derived data, is therefore promising for a variety of clinical applications requiring long-term deep sleep monitoring., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Song et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Published: 2023
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38. Sources of Variation in the Spectral Slope of the Sleep EEG.

Author: Kozhemiako N, Mylonas D, Pan JQ, Prerau MJ, Redline S, and Purcell SM
Subjects: Female, Humans, Male, Reproducibility of Results, Sleep, Sleep, REM, Electroencephalography, Sleep, Slow-Wave
Abstract: The 1/ f spectral slope of the electroencephalogram (EEG) estimated in the γ frequency range has been proposed as an arousal marker that differentiates wake, nonrapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep. Here, we sought to replicate and extend these findings in a large sample, providing a comprehensive characterization of how slope changes with age, sex, and its test-retest reliability as well as potential confounds that could affect the slope estimation. We used 10,255 whole-night polysomnograms (PSGs) from the National Sleep Research Resource (NSRR). All preprocessing steps were performed using an open-source Luna package and the spectral slope was estimated by fitting log-log linear regression models on the absolute power from 30 to 45 Hz separately for wake, NREM, and REM stages. We confirmed that the mean spectral slope grows steeper going from wake to NREM to REM sleep. We found that the choice of mastoid referencing scheme modulated the extent to which electromyogenic, or electrocardiographic artifacts were likely to bias 30- to 45-Hz slope estimates, as well as other sources of technical, device-specific bias. Nonetheless, within individuals, slope estimates were relatively stable over time. Both cross-sectionally and longitudinal, slopes tended to become shallower with increasing age, particularly for REM sleep; males tended to show flatter slopes than females across all states. Our findings support that spectral slope can be a valuable arousal marker for both clinical and research endeavors but also underscore the importance of considering interindividual variation and multiple methodological aspects related to its estimation., (Copyright © 2022 Kozhemiako et al.)
Published: 2022
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39. Impact of chronic sleep restriction on sleep continuity, sleep structure, and neurobehavioral performance.

Author: Xin Q, Yuan RK, Zitting KM, Wang W, Purcell SM, Vujovic N, Ronda JM, Quan SF, Williams JS, Buxton OM, Duffy JF, and Czeisler CA
Subjects: Humans, Polysomnography, Sleep, Time Factors, Sleep Deprivation complications, Sleep Deprivation psychology, Sleep Initiation and Maintenance Disorders complications
Abstract: Chronic sleep restriction (CSR) has been associated with adverse effects including cognitive impairment and increased risk of diabetes and cardiovascular disease. Yet, sleep restriction therapy is an essential component of most behavioral treatments for insomnia. Moreover, little is known about the impact of CSR on sleep continuity and structure in healthy people whose need for sleep is satiated. We investigated the impact of CSR on sleep continuity and structure in nine healthy participants. They had 4 nights of sleep extension, 2 nights of post-extension sleep, 21 nights of CSR (5/5.6-hour time-in-bed), and 9 nights of recovery sleep. Compared to postextension sleep, during CSR sleep duration was reduced by 95.4 ± 21.2 min per night, Slow-Wave Activity was significantly increased, and sleep was more consolidated. During recovery, sleep duration was increased by 103.3 ± 23.8 min compared to CSR, and the CSR-induced increase in Slow-Wave Activity persisted, particularly after the 5-hour exposure. Yet, we found that sustained vigilant attention was not fully recovered even after nine nights of recovery sleep. Our results suggest that CSR improves traditional metrics of sleep quality and may have a persistent impact on sleep depth, which is consistent with the reported benefits on sleep continuity and structure of sleep restriction therapy. However, these improvements in traditional metrics of sleep quality were associated with deterioration rather than improvement in neurobehavioral performance, demonstrating that sleep duration should be included in assessments of sleep quality. These results have implications for the long-term use of sleep restriction in the behavioral treatment of insomnia. Clinical Trial Registration: Impact of Chronic Circadian Disruption vs. Chronic Sleep Restriction on Metabolism (https://clinicaltrials.gov/ct2/show/; #NCT02171273)., (© The Author(s) 2022. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Published: 2022
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40. Non-rapid eye movement sleep and wake neurophysiology in schizophrenia.

Author: Kozhemiako N, Wang J, Jiang C, Wang LA, Gai G, Zou K, Wang Z, Yu X, Zhou L, Li S, Guo Z, Law R, Coleman J, Mylonas D, Shen L, Wang G, Tan S, Qin S, Huang H, Murphy M, Stickgold R, Manoach D, Zhou Z, Zhu W, Hal MH, Purcell SM, and Pan JQ
Subjects: Electroencephalography, Humans, Neurophysiology, Polysomnography, Sleep physiology, Schizophrenia
Abstract: Motivated by the potential of objective neurophysiological markers to index thalamocortical function in patients with severe psychiatric illnesses, we comprehensively characterized key non-rapid eye movement (NREM) sleep parameters across multiple domains, their interdependencies, and their relationship to waking event-related potentials and symptom severity. In 72 schizophrenia (SCZ) patients and 58 controls, we confirmed a marked reduction in sleep spindle density in SCZ and extended these findings to show that fast and slow spindle properties were largely uncorrelated. We also describe a novel measure of slow oscillation and spindle interaction that was attenuated in SCZ. The main sleep findings were replicated in a demographically distinct sample, and a joint model, based on multiple NREM components, statistically predicted disease status in the replication cohort. Although also altered in patients, auditory event-related potentials elicited during wake were unrelated to NREM metrics. Consistent with a growing literature implicating thalamocortical dysfunction in SCZ, our characterization identifies independent NREM and wake EEG biomarkers that may index distinct aspects of SCZ pathophysiology and point to multiple neural mechanisms underlying disease heterogeneity. This study lays the groundwork for evaluating these neurophysiological markers, individually or in combination, to guide efforts at treatment and prevention as well as identifying individuals most likely to benefit from specific interventions., Competing Interests: NK, JW, CJ, LW, GG, KZ, ZW, XY, LZ, SL, ZG, RL, JC, DM, LS, GW, ST, SQ, HH, MM, RS, DM, ZZ, WZ, MH, SP, JP No competing interests declared, (© 2022, Kozhemiako et al.)
Published: 2022
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41. Surface Structure of Alkyl/Fluoroalkylimidazolium Ionic-Liquid Mixtures.

Author: Purcell SM, Lane PD, D'Andrea L, Elstone NS, Bruce DW, Slattery JM, Smoll EJ Jr, Greaves SJ, Costen ML, Minton TK, and McKendrick KG
Abstract: The gas-liquid interface of ionic liquids (ILs) is critically important in many applications, for example, in supported IL phase (SILP) catalysis. Methods to investigate the interfacial structure in these systems will allow their performance to be improved in a rational way. In this study, reactive-atom scattering (RAS), surface tension measurements, and molecular dynamics (MD) simulations were used to study the vacuum interface of mixtures of partially fluorinated and normal alkyl ILs. The underlying aim was to understand whether fluorinated IL ions could be used as additives to modify the surface structure of one of the most widely used families of alkyl ILs. The series of ILs 1-alkyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([C n mim][Tf 2 N]) with n = 4-12 were mixed with a fixed-length, semiperfluorinated analogue (1 H ,1 H ,2 H ,2 H -perfluorooctyl)-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([C 8 mimF 13 ][Tf 2 N]), forming [C n mim] (1- x ) [C 8 mimF 13 ] x [Tf 2 N] mixtures, where x is the bulk mole fraction of the fluorinated component. The RAS-LIF method combined O-atom projectiles with laser-induced fluorescence (LIF) detection of the product OH as a measure of surface exposure of the alkyl chains. For [C 8 mim] (1- x ) [C 8 mimF 13 ] x [Tf 2 N] mixtures, RAS-LIF OH yields are below those expected from stoichiometry. There are quantitatively consistent negative deviations from linearity of the surface tension. Both results imply that the lower-surface-tension fluoroalkyl material dominates the surface. A similar deficit is found for alkyl chain lengths n = 4, 6, 8, and 12 and for all (nonzero) x investigated by RAS-LIF. Accessible-surface-area (ASA) analyses of the MD simulations for [C n mim] (1- x ) [C 8 mimF 13 ] x [Tf 2 N] mixtures qualitatively reproduce the same primary effect of fluoro-chain predominance of the surface over most of the range of n . However, there are significant quantitative discrepancies between MD ASA predictions and experiment relating to the strength of any n -dependence of the relative alkyl coverage at fixed x , and on the x -dependence at fixed n . These discrepancies are discussed in the context of detailed examinations of the surface structures predicted in the MD simulations. Potential explanations, beyond experimental artifacts, include inadequacies in the classical force fields used in the MD simulations or the inability of simple ASA algorithms to capture dynamical factors that influence RAS-LIF yields.
Published: 2022
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42. Upregulated heme biosynthesis increases obstructive sleep apnea severity: a pathway-based Mendelian randomization study.

Author: Wang H, Kurniansyah N, Cade BE, Goodman MO, Chen H, Gottlieb DJ, Gharib SA, Purcell SM, Lin X, Saxena R, Zhu X, Durda P, Tracy R, Liu Y, Taylor KD, Johnson WC, Gabriel S, Smith JD, Aguet F, Ardlie K, Blackwell T, Reiner AP, Rotter JI, Rich SS, Redline S, and Sofer T
Subjects: Aged, Datasets as Topic, Female, Genetic Predisposition to Disease, Humans, Iron metabolism, Male, Mendelian Randomization Analysis, Middle Aged, Polysomnography, Quantitative Trait Loci, Severity of Illness Index, Sleep Apnea, Obstructive blood, Sleep Apnea, Obstructive diagnosis, Sleep Apnea, Obstructive genetics, Up-Regulation, Heme biosynthesis, Metabolic Networks and Pathways genetics, Sleep Apnea, Obstructive epidemiology
Abstract: Obstructive sleep apnea (OSA) is a common disorder associated with increased risk of cardiovascular disease and mortality. Iron and heme metabolism, implicated in ventilatory control and OSA comorbidities, was associated with OSA phenotypes in recent admixture mapping and gene enrichment analyses. However, its causal contribution was unclear. In this study, we performed pathway-level transcriptional Mendelian randomization (MR) analysis to investigate the causal relationships between iron and heme related pathways and OSA. In primary analysis, we examined the expression level of four iron/heme Reactome pathways as exposures and four OSA traits as outcomes using cross-tissue cis-eQTLs from the Genotype-Tissue Expression portal and published genome-wide summary statistics of OSA. We identify a significant putative causal association between up-regulated heme biosynthesis pathway with higher sleep time percentage of hypoxemia (p = 6.14 × 10 -3 ). This association is supported by consistency of point estimates in one-sample MR in the Multi-Ethnic Study of Atherosclerosis using high coverage DNA and RNA sequencing data generated by the Trans-Omics for Precision Medicine project. Secondary analysis for 37 additional iron/heme Gene Ontology pathways did not reveal any significant causal associations. This study suggests a causal association between increased heme biosynthesis and OSA severity., (© 2022. The Author(s).)
Published: 2022
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43. Lipodystrophies

Author: Quinn K, Chauhan S, and Purcell SM
Abstract: Lipodystrophies are the category of conditions that share the common finding of a reduction in subcutaneous fat. There are multiple subtypes of lipodystrophy, which may be either congenital or acquired and vary in the distribution of fat loss. Although all are relatively rare in incidence, acquired variants have become more common as an adverse effect of certain medications and iatrogenic mechanisms. Regardless of subtype, decreases in overall adipose burden may lead to metabolic complications, with subsequent increases in morbidity and mortality in lipodystrophy patients. Congenital Generalized Lipodystrophy Congenital generalized lipodystrophy, sometimes referred to as Berardinelli-Seip syndrome, is an uncommon lipodystrophy variant with significant and sometimes near-total fat loss. Familial Partial Lipodystrophy Familial partial lipodystrophy is most often an autosomal dominant condition with fat loss primarily involving the extremities, more commonly lower than upper. Acquired Generalized Lipodystrophy Acquired generalized lipodystrophy is an extremely rare condition of widespread subcutaneous fat loss. Acquired Partial Lipodystrophy Acquired partial lipodystrophy, or Barraquer-Simons syndrome, is characterized by gradual loss of fat from the upper body and truncal region during childhood. Over the past few decades, however, highly active anti-retroviral therapy induced lipodystrophy has become the most common form of acquired partial lipodystrophy., (Copyright © 2022, StatPearls Publishing LLC.)
Published: 2022

44. Nephrogenic Systemic Fibrosis in the Setting of Transient Renal Insufficiency.

Author: Dinh H, Phan J, Lountzis NI, and Purcell SM
Subjects: Contrast Media adverse effects, Gadolinium adverse effects, Humans, Magnetic Resonance Imaging, Nephrogenic Fibrosing Dermopathy chemically induced, Nephrogenic Fibrosing Dermopathy diagnosis, Renal Insufficiency diagnosis
Abstract: Nephrogenic systemic fibrosis (NSF) is a rare disease that can present in patients with kidney injury who have been exposed to gadolinium-based contrast agents (GBCAs). These patients can easily be misdiagnosed as having another disease because they do not fit the usual presentation of being on hemodialysis. We report a case of NSF occurring in a patient with resolved transient renal insufficiency and no history of chronic renal disease.
Published: 2021
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45. Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program.

Author: Cade BE, Lee J, Sofer T, Wang H, Zhang M, Chen H, Gharib SA, Gottlieb DJ, Guo X, Lane JM, Liang J, Lin X, Mei H, Patel SR, Purcell SM, Saxena R, Shah NA, Evans DS, Hanis CL, Hillman DR, Mukherjee S, Palmer LJ, Stone KL, Tranah GJ, Abecasis GR, Boerwinkle EA, Correa A, Cupples LA, Kaplan RC, Nickerson DA, North KE, Psaty BM, Rotter JI, Rich SS, Tracy RP, Vasan RS, Wilson JG, Zhu X, and Redline S
Subjects: Alleles, Chromatin Immunoprecipitation Sequencing, Female, Gene Expression Regulation, Genotype, Humans, Male, National Heart, Lung, and Blood Institute (U.S.), Phenotype, Precision Medicine methods, Research, Signal Transduction, Sleep Apnea Syndromes metabolism, United States, Genetic Association Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Sleep Apnea Syndromes diagnosis, Sleep Apnea Syndromes etiology, Whole Genome Sequencing
Abstract: Background: Sleep-disordered breathing is a common disorder associated with significant morbidity. The genetic architecture of sleep-disordered breathing remains poorly understood. Through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, we performed the first whole-genome sequence analysis of sleep-disordered breathing., Methods: The study sample was comprised of 7988 individuals of diverse ancestry. Common-variant and pathway analyses included an additional 13,257 individuals. We examined five complementary traits describing different aspects of sleep-disordered breathing: the apnea-hypopnea index, average oxyhemoglobin desaturation per event, average and minimum oxyhemoglobin saturation across the sleep episode, and the percentage of sleep with oxyhemoglobin saturation < 90%. We adjusted for age, sex, BMI, study, and family structure using MMSKAT and EMMAX mixed linear model approaches. Additional bioinformatics analyses were performed with MetaXcan, GIGSEA, and ReMap., Results: We identified a multi-ethnic set-based rare-variant association (p = 3.48 × 10 -8 ) on chromosome X with ARMCX3. Additional rare-variant associations include ARMCX3-AS1, MRPS33, and C16orf90. Novel common-variant loci were identified in the NRG1 and SLC45A2 regions, and previously associated loci in the IL18RAP and ATP2B4 regions were associated with novel phenotypes. Transcription factor binding site enrichment identified associations with genes implicated with respiratory and craniofacial traits. Additional analyses identified significantly associated pathways., Conclusions: We have identified the first gene-based rare-variant associations with objectively measured sleep-disordered breathing traits. Our results increase the understanding of the genetic architecture of sleep-disordered breathing and highlight associations in genes that modulate lung development, inflammation, respiratory rhythmogenesis, and HIF1A-mediated hypoxic response., (© 2021. The Author(s).)
Published: 2021
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46. Sleep and Big Data: harnessing data, technology, and analytics for monitoring sleep and improving diagnostics, prediction, and interventions-an era for Sleep-Omics?

Author: Redline S and Purcell SM
Subjects: Sleep, Technology
Published: 2021
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47. Exuberant Lymphomatoid Papulosis of the Head and Upper Trunk.

Author: Hemperly S, Lountzis N, and Purcell SM
Subjects: Humans, Torso, Hodgkin Disease, Lymphomatoid Papulosis diagnosis, Skin Neoplasms diagnosis
Published: 2021
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48. Orange palpebral spots.

Author: Blannett S, Swink SM, and Purcell SM
Subjects: Animals, Eyelids, Pigmentation, Citrus sinensis, Poecilia
Published: 2021
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49. Publisher Correction: Macro and micro sleep architecture and cognitive performance in older adults.

Author: Djonlagic I, Mariani S, Fitzpatrick AL, Van Der Klei VMGTH, Johnson DA, Wood AC, Seeman T, Nguyen HT, Prerau MJ, Luchsinger JA, Dzierzewski JM, Rapp SR, Tranah GJ, Yaffe K, Burdick KE, Stone KL, Redline S, and Purcell SM
Published: 2021
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50. Macro and micro sleep architecture and cognitive performance in older adults.

Author: Djonlagic I, Mariani S, Fitzpatrick AL, Van Der Klei VMGTH, Johnson DA, Wood AC, Seeman T, Nguyen HT, Prerau MJ, Luchsinger JA, Dzierzewski JM, Rapp SR, Tranah GJ, Yaffe K, Burdick KE, Stone KL, Redline S, and Purcell SM
Subjects: Age Factors, Aged, Aged, 80 and over, Aging physiology, Case-Control Studies, Electroencephalography, Humans, Male, Metabolic Syndrome physiopathology, Middle Aged, Sleep, REM physiology, Cognition physiology, Sleep physiology
Abstract: We sought to determine which facets of sleep neurophysiology were most strongly linked to cognitive performance in 3,819 older adults from two independent cohorts, using whole-night electroencephalography. From over 150 objective sleep metrics, we identified 23 that predicted cognitive performance, and processing speed in particular, with effects that were broadly independent of gross changes in sleep quality and quantity. These metrics included rapid eye movement duration, features of the electroencephalography power spectra derived from multivariate analysis, and spindle and slow oscillation morphology and coupling. These metrics were further embedded within broader associative networks linking sleep with aging and cardiometabolic disease: individuals who, compared with similarly aged peers, had better cognitive performance tended to have profiles of sleep metrics more often seen in younger, healthier individuals. Taken together, our results point to multiple facets of sleep neurophysiology that track coherently with underlying, age-dependent determinants of cognitive and physical health trajectories in older adults.
Published: 2021
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