Browsing by Author "Schofield, Peter R."
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Item 15 Years of Longitudinal Genetic, Clinical, Cognitive, Imaging, and Biochemical Measures in DIAN(medRxiv, 2024-08-09) Daniels, Alisha J.; McDade, Eric; Llibre-Guerra, Jorge J.; Xiong, Chengjie; Perrin, Richard J.; Ibanez, Laura; Supnet-Bell, Charlene; Cruchaga, Carlos; Goate, Alison; Renton, Alan E.; Benzinger, Tammie L. S.; Gordon, Brian A.; Hassenstab, Jason; Karch, Celeste; Popp, Brent; Levey, Allan; Morris, John; Buckles, Virginia; Allegri, Ricardo F.; Chrem, Patricio; Berman, Sarah B.; Chhatwal, Jasmeer P.; Farlow, Martin R.; Fox, Nick C.; Day, Gregory S.; Ikeuchi, Takeshi; Jucker, Mathias; Lee, Jae-Hong; Levin, Johannes; Lopera, Francisco; Takada, Leonel; Sosa, Ana Luisa; Martins, Ralph; Mori, Hiroshi; Noble, James M.; Salloway, Stephen; Huey, Edward; Rosa-Neto, Pedro; Sánchez-Valle, Raquel; Schofield, Peter R.; Roh, Jee Hoon; Bateman, Randall J.; Dominantly Inherited Alzheimer Network; Neurology, School of MedicineThis manuscript describes and summarizes the Dominantly Inherited Alzheimer Network Observational Study (DIAN Obs), highlighting the wealth of longitudinal data, samples, and results from this human cohort study of brain aging and a rare monogenic form of Alzheimer's disease (AD). DIAN Obs is an international collaborative longitudinal study initiated in 2008 with support from the National Institute on Aging (NIA), designed to obtain comprehensive and uniform data on brain biology and function in individuals at risk for autosomal dominant AD (ADAD). ADAD gene mutations in the amyloid protein precursor (APP), presenilin 1 (PSEN1), or presenilin 2 (PSEN2) genes are deterministic causes of ADAD, with virtually full penetrance, and a predictable age at symptomatic onset. Data and specimens collected are derived from full clinical assessments, including neurologic and physical examinations, extensive cognitive batteries, structural and functional neuro-imaging, amyloid and tau pathological measures using positron emission tomography (PET), flurordeoxyglucose (FDG) PET, cerebrospinal fluid and blood collection (plasma, serum, and whole blood), extensive genetic and multi-omic analyses, and brain donation upon death. This comprehensive evaluation of the human nervous system is performed longitudinally in both mutation carriers and family non-carriers, providing one of the deepest and broadest evaluations of the human brain across decades and through AD progression. These extensive data sets and samples are available for researchers to address scientific questions on the human brain, aging, and AD.Item Assessment of First and Second Degree Relatives of Individuals With Bipolar Disorder Shows Increased Genetic Risk Scores in Both Affected Relatives and Young At-Risk Individuals(Wiley, 2015-10) Fullerton, Janice M.; Koller, Daniel L.; Edenberg, Howard J.; Foroud, Tatiana; Liu, Hai; Glowinski, Anne L.; McInnis, Melvin G.; Wilcox, Holly C.; Frankland, Andrew; Roberts, Gloria; Schofield, Peter R.; Mitchell, Philip B.; Nurnberger, John I.; Department of Biochemistry and Molecular Biology, IU School of MedicineRecent studies have revealed the polygenic nature of bipolar disorder (BP), and identified common risk variants associated with illness. However, the role of common polygenic risk in multiplex families has not previously been examined. The present study examined 249 European-ancestry families from the NIMH Genetics Initiative sample, comparing subjects with narrowly defined BP (excluding bipolar II and recurrent unipolar depression; n = 601) and their adult relatives without BP (n = 695). Unrelated adult controls (n = 266) were from the NIMH TGEN control dataset. We also examined a prospective cohort of young (12–30 years) offspring and siblings of individuals with BPI and BPII disorder (at risk; n = 367) and psychiatrically screened controls (n = 229), ascertained from five sites in the US and Australia and assessed with standardized clinical protocols. Thirty-two disease-associated SNPs from the PGC-BP Working Group report (2011) were genotyped and additive polygenic risk scores (PRS) derived. We show increased PRS in adult cases compared to unrelated controls (P = 3.4 × 10−5, AUC = 0.60). In families with a high-polygenic load (PRS score ≥32 in two or more subjects), PRS distinguished cases with BPI/SAB from other relatives (P = 0.014, RR = 1.32). Secondly, a higher PRS was observed in at-risk youth, regardless of affected status, compared to unrelated controls (GEE-χ2 = 5.15, P = 0.012). This report is the first to explore common polygenic risk in multiplex families, albeit using only a small number of robustly associated risk variants. We show that individuals with BP have a higher load of common disease-associated variants than unrelated controls and first-degree relatives, and illustrate the potential utility of PRS assessment in a family context.Item Association of BDNF Val66Met With Tau Hyperphosphorylation and Cognition in Dominantly Inherited Alzheimer Disease(American Medical Association, 2022-03-01) Lim, Yen Ying; Maruff, Paul; Barthélemy, Nicolas R.; Goate, Alison; Hassenstab, Jason; Sato, Chihiro; Fagan, Anne M.; Benzinger, Tammie L. S.; Xiong, Chengjie; Cruchaga, Carlos; Levin, Johannes; Farlow, Martin R.; Graff-Radford, Neill R.; Laske, Christoph; Masters, Colin L.; Salloway, Stephen; Schofield, Peter R.; Morris, John C.; Bateman, Randall J.; McDade, Eric; Dominantly Inherited Alzheimer Network; Neurology, School of MedicineImportance: Allelic variation in the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism moderates increases in cerebrospinal fluid (CSF) levels of tau and phosphorylated tau 181 (p-tau181), measured using immunoassay, and cognitive decline in presymptomatic dominantly inherited Alzheimer disease (DIAD). Advances in mass spectrometry show that CSF tau phosphorylation occupancy at threonine 181 and 217 (p-tau181/tau181, p-tau217/tau217) increases with initial β-amyloid (Aβ) aggregation, while phosphorylation occupancy at threonine 205 (p-tau205/tau205) and level of total tau increase when brain atrophy and clinical symptoms become evident. Objective: To determine whether site-specific tau phosphorylation occupancy (ratio of phosphorylated to unphosphorylated tau) is associated with BDNF Val66Met in presymptomatic and symptomatic DIAD. Design, setting, and participants: This cross-sectional cohort study included participants from the Dominantly Inherited Alzheimer Network (DIAN) and Aβ-positive cognitively normal older adults in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Data were collected from 2009 through 2018 at multicenter clinical sites in the United States, United Kingdom, and Australia, with no follow-up. DIAN participants provided a CSF sample and completed clinical and cognitive assessments. Data analysis was conducted between March 2020 and March 2021. Main outcomes and measures: Mass spectrometry analysis was used to determine site-specific tau phosphorylation level; tau levels were also measured using immunoassay. Episodic memory and global cognitive composites were computed. Results: Of 374 study participants, 144 were mutation noncarriers, 156 were presymptomatic mutation carriers, and 74 were symptomatic carriers. Of the 527 participants in the network, 153 were excluded because their CSF sample, BDNF status, or both were unavailable. Also included were 125 Aβ-positive cognitively normal older adults in the ADNI. The mean (SD) age of DIAD participants was 38.7 (10.9) years; 43% were women. The mean (SD) age of participants with preclinical sporadic AD was 74.8 (5.6) years; 52% were women. In presymptomatic mutation carriers, compared with Val66 homozygotes, Met66 carriers showed significantly poorer episodic memory (d = 0.62; 95% CI, 0.28-0.95), lower hippocampal volume (d = 0.40; 95% CI, 0.09-0.71), and higher p-tau217/tau217 (d = 0.64; 95% CI, 0.30-0.97), p-tau181/tau181 (d = 0.65; 95% CI, 0.32-0.99), and mass spectrometry total tau (d = 0.43; 95% CI, 0.10-0.76). In symptomatic mutation carriers, Met66 carriers showed significantly poorer global cognition (d = 1.17; 95% CI, 0.65-1.66) and higher p-tau217/tau217 (d = 0.53; 95% CI, 0.05-1.01), mass spectrometry total tau (d = 0.78; 95% CI, 0.28-1.25), and p-tau205/tau205 (d = 0.97; 95% CI, 0.46-1.45), when compared with Val66 homozygotes. In preclinical sporadic AD, Met66 carriers showed poorer episodic memory (d = 0.39; 95% CI, 0.00-0.77) and higher total tau (d = 0.45; 95% CI, 0.07-0.84) and p-tau181 (d = 0.46; 95% CI, 0.07-0.85). Conclusions and relevance: In DIAD, clinical disease stage and BDNF Met66 were associated with cognitive impairment and levels of site-specific tau phosphorylation. This suggests that pharmacological strategies designed to increase neurotrophic support in the presymptomatic stages of AD may be beneficial.Item Autosomal dominant and sporadic late onset Alzheimer's disease share a common in vivo pathophysiology(Oxford University Press, 2022) Morris, John C.; Weiner, Michael; Xiong, Chengjie; Beckett, Laurel; Coble, Dean; Saito, Naomi; Aisen, Paul S.; Allegri, Ricardo; Benzinger, Tammie L. S.; Berman, Sarah B.; Cairns, Nigel J.; Carrillo, Maria C.; Chui, Helena C.; Chhatwal, Jasmeer P.; Cruchaga, Carlos; Fagan, Anne M.; Farlow, Martin; Fox, Nick C.; Ghetti, Bernardino; Goate, Alison M.; Gordon, Brian A.; Graff-Radford, Neill; Day, Gregory S.; Hassenstab, Jason; Ikeuchi, Takeshi; Jack, Clifford R.; Jagust, William J.; Jucker, Mathias; Levin, Johannes; Massoumzadeh, Parinaz; Masters, Colin L.; Martins, Ralph; McDade, Eric; Mori, Hiroshi; Noble, James M.; Petersen, Ronald C.; Ringman, John M.; Salloway, Stephen; Saykin, Andrew J.; Schofield, Peter R.; Shaw, Leslie M.; Toga, Arthur W.; Trojanowski, John Q.; Vöglein, Jonathan; Weninger, Stacie; Bateman, Randall J.; Buckles, Virginia D.; Dominantly Inherited Alzheimer Network; Alzheimer’s Disease Neuroimaging and Initiative; Neurology, School of MedicineThe extent to which the pathophysiology of autosomal dominant Alzheimer's disease corresponds to the pathophysiology of 'sporadic' late onset Alzheimer's disease is unknown, thus limiting the extrapolation of study findings and clinical trial results in autosomal dominant Alzheimer's disease to late onset Alzheimer's disease. We compared brain MRI and amyloid PET data, as well as CSF concentrations of amyloid-β42, amyloid-β40, tau and tau phosphorylated at position 181, in 292 carriers of pathogenic variants for Alzheimer's disease from the Dominantly Inherited Alzheimer Network, with corresponding data from 559 participants from the Alzheimer's Disease Neuroimaging Initiative. Imaging data and CSF samples were reprocessed as appropriate to guarantee uniform pipelines and assays. Data analyses yielded rates of change before and after symptomatic onset of Alzheimer's disease, allowing the alignment of the ∼30-year age difference between the cohorts on a clinically meaningful anchor point, namely the participant age at symptomatic onset. Biomarker profiles were similar for both autosomal dominant Alzheimer's disease and late onset Alzheimer's disease. Both groups demonstrated accelerated rates of decline in cognitive performance and in regional brain volume loss after symptomatic onset. Although amyloid burden accumulation as determined by PET was greater after symptomatic onset in autosomal dominant Alzheimer's disease than in late onset Alzheimer's disease participants, CSF assays of amyloid-β42, amyloid-β40, tau and p-tau181 were largely overlapping in both groups. Rates of change in cognitive performance and hippocampal volume loss after symptomatic onset were more aggressive for autosomal dominant Alzheimer's disease participants. These findings suggest a similar pathophysiology of autosomal dominant Alzheimer's disease and late onset Alzheimer's disease, supporting a shared pathobiological construct.Item Autosomal Dominantly Inherited Alzheimer Disease: Analysis of genetic subgroups by Machine Learning(Elsevier, 2020-06) Castillo-Barne, Diego; Su, Li; Ramírez, Javier; Salas-Gonzalez, Diego; Martinez-Murcia, Francisco J.; Illan, Ignacio A.; Segovia, Fermin; Ortiz, Andres; Cruchaga, Carlos; Farlow, Martin R.; Xiong, Chengjie; Graff-Radford, Neil R.; Schofield, Peter R.; Masters, Colin L.; Salloway, Stephen; Jucker, Mathias; Mori, Hiroshi; Levin, Johannes; Gorriz, Juan M.; Neurology, School of MedicineDespite subjects with Dominantly-Inherited Alzheimer's Disease (DIAD) represent less than 1% of all Alzheimer's Disease (AD) cases, the Dominantly Inherited Alzheimer Network (DIAN) initiative constitutes a strong impact in the understanding of AD disease course with special emphasis on the presyptomatic disease phase. Until now, the 3 genes involved in DIAD pathogenesis (PSEN1, PSEN2 and APP) have been commonly merged into one group (Mutation Carriers, MC) and studied using conventional statistical analysis. Comparisons between groups using null-hypothesis testing or longitudinal regression procedures, such as the linear-mixed-effects models, have been assessed in the extant literature. Within this context, the work presented here performs a comparison between different groups of subjects by considering the 3 genes, either jointly or separately, and using tools based on Machine Learning (ML). This involves a feature selection step which makes use of ANOVA followed by Principal Component Analysis (PCA) to determine which features would be realiable for further comparison purposes. Then, the selected predictors are classified using a Support-Vector-Machine (SVM) in a nested k-Fold cross-validation resulting in maximum classification rates of 72-74% using PiB PET features, specially when comparing asymptomatic Non-Carriers (NC) subjects with asymptomatic PSEN1 Mutation-Carriers (PSEN1-MC). Results obtained from these experiments led to the idea that PSEN1-MC might be considered as a mixture of two different subgroups including: a first group whose patterns were very close to NC subjects, and a second group much more different in terms of imaging patterns. Thus, using a k-Means clustering algorithm it was determined both subgroups and a new classification scenario was conducted to validate this process. The comparison between each subgroup vs. NC subjects resulted in classification rates around 80% underscoring the importance of considering DIAN as an heterogeneous entity.Item Axonal damage and inflammation response are biological correlates of decline in small-world values: a cohort study in autosomal dominant Alzheimer's disease(Oxford University Press, 2024-10-09) Vermunt, Lisa; Sutphen, Courtney L.; Dicks, Ellen; de Leeuw, Diederick M.; Allegri, Ricardo F.; Berman, Sarah B.; Cash, David M.; Chhatwal, Jasmeer P.; Cruchaga, Carlos; Day, Gregory S.; Ewers, Michael; Farlow, Martin R.; Fox, Nick C.; Ghetti, Bernardino; Graff-Radford, Neill R.; Hassenstab, Jason; Jucker, Mathias; Karch, Celeste M.; Kuhle, Jens; Laske, Christoph; Levin, Johannes; Masters, Colin L.; McDade, Eric; Mori, Hiroshi; Morris, John C.; Perrin, Richard J.; Preische, Oliver; Schofield, Peter R.; Suárez-Calvet, Marc; Xiong, Chengjie; Scheltens, Philip; Teunissen, Charlotte E.; Visser, Pieter Jelle; Bateman, Randall J.; Benzinger, Tammie L. S.; Fagan, Anne M.; Gordon, Brian A.; Tijms, Betty M.; Pathology and Laboratory Medicine, School of MedicineThe grey matter of the brain develops and declines in coordinated patterns during the lifespan. Such covariation patterns of grey matter structure can be quantified as grey matter networks, which can be measured with magnetic resonance imaging. In Alzheimer's disease, the global organization of grey matter networks becomes more random, which is captured by a decline in the small-world coefficient. Such decline in the small-world value has been robustly associated with cognitive decline across clinical stages of Alzheimer's disease. The biological mechanisms causing this decline in small-world values remain unknown. Cerebrospinal fluid (CSF) protein biomarkers are available for studying diverse pathological mechanisms in humans and can provide insight into decline. We investigated the relationships between 10 CSF proteins and small-world coefficient in mutation carriers (N = 219) and non-carriers (N = 136) of the Dominantly Inherited Alzheimer Network Observational study. Abnormalities in Amyloid beta, Tau, synaptic (Synaptosome associated protein-25, Neurogranin) and neuronal calcium-sensor protein (Visinin-like protein-1) preceded loss of small-world coefficient by several years, while increased levels in CSF markers for inflammation (Chitinase-3-like protein 1) and axonal injury (Neurofilament light) co-occurred with decreasing small-world values. This suggests that axonal loss and inflammation play a role in structural grey matter network changes.Item BDNF Val66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer’s disease(Oxford, 2016-10) Lim, Yen Ying; Hassenstab, Jason; Cruchaga, Carlos; Goate, Alison; Fagan, Anne M.; Benzinger, Tammie L. S.; Maruff, Paul; Snyder, Peter J.; Masters, Colin L.; Allegri, Ricardo; Chhatwal, Jasmeer; Farlow, Martin R.; Graff-Radford, Neill R.; Laske, Christoph; Levin, Johannes; McDade, Eric; Ringman, John M.; Rossor, Martin N.; Salloway, Stephen; Schofield, Peter R.; Holtzman, David M.; Morris, John C.; Bateman, Randall J.; Department of Neurology, IU School of MedicineThe brain-derived neurotrophic factor ( BDNF ) Val66Met polymorphism is implicated in synaptic excitation and neuronal integrity, and has previously been shown to moderate amyloid-β-related memory decline and hippocampal atrophy in preclinical sporadic Alzheimer’s disease. However, the effect of BDNF in autosomal dominant Alzheimer’s disease is unknown. We aimed to determine the effect of BDNF Val66Met on cognitive function, hippocampal function, tau and amyloid-β in preclinical autosomal dominant Alzheimer’s disease. We explored effects of apolipoprotein E ( APOE ) ε4 on these relationships. The Dominantly Inherited Alzheimer Network conducted clinical, neuropsychological, genetic, biomarker and neuroimaging measures at baseline in 131 mutation non-carriers and 143 preclinical autosomal dominant Alzheimer’s disease mutation carriers on average 12 years before clinical symptom onset. BDNF genotype data were obtained for mutation carriers (95 Val 66 homozygotes, 48 Met 66 carriers). Among preclinical mutation carriers, Met 66 carriers had worse memory performance, lower hippocampal glucose metabolism and increased levels of cerebrospinal fluid tau and phosphorylated tau (p-tau) than Val 66 homozygotes. Cortical amyloid-β and cerebrospinal fluid amyloid-β 42 levels were significantly different from non-carriers but did not differ between preclinical mutation carrier Val 66 homozygotes and Met 66 carriers. There was an effect of APOE on amyloid-β levels, but not cognitive function, glucose metabolism or tau. As in sporadic Alzheimer’s disease, the deleterious effects of amyloid-β on memory, hippocampal function, and tau in preclinical autosomal dominant Alzheimer’s disease mutation carriers are greater in Met 66 carriers. To date, this is the only genetic factor found to moderate downstream effects of amyloid-β in autosomal dominant Alzheimer’s disease.Item Cerebral amyloidosis associated with cognitive decline in autosomal dominant Alzheimer disease(American Academy of Neurology, 2015-09) Wang, Fen; Gordon, Brian A.; Ryman, Davis C.; Ma, Shengmei; Xiong, Chengjie; Hassenstab, Jason; Goate, Alison; Fagan, Anne M.; Cairns, Nigel J.; Marcus, Daniel S.; McDade, Eric; Ringman, John M.; Graff-Radford, Neill R.; Ghetti, Bernardino; Farlow, Martin R.; Sperling, Reisa; Salloway, Steve; Schofield, Peter R.; Masters, Colin L.; Martins, Ralph N.; Rossor, Martin N. N.; Jucker, Mathias; Danek, Adrian; Förster, Stefan; Lane, Christopher A.S.; Morris, John C.; Benzinger, Tammie L. S.; Bateman, Randall J.; Department of Neurology, IU School of MedicineOBJECTIVE: To investigate the associations of cerebral amyloidosis with concurrent cognitive performance and with longitudinal cognitive decline in asymptomatic and symptomatic stages of autosomal dominant Alzheimer disease (ADAD). METHODS: Two hundred sixty-three participants enrolled in the Dominantly Inherited Alzheimer Network observational study underwent neuropsychological evaluation as well as PET scans with Pittsburgh compound B. One hundred twenty-one participants completed at least 1 follow-up neuropsychological evaluation. Four composite cognitive measures representing global cognition, episodic memory, language, and working memory were generated using z scores from a battery of 13 standard neuropsychological tests. General linear mixed-effects models were used to investigate the relationship between baseline cerebral amyloidosis and baseline cognitive performance and whether baseline cerebral amyloidosis predicts cognitive change over time (mean follow-up 2.32 years ± 0.92, range 0.89-4.19) after controlling for estimated years from expected symptom onset, APOE ε4 allelic status, and education. RESULTS: In asymptomatic mutation carriers, amyloid burden was not associated with baseline cognitive functioning but was significantly predictive of longitudinal decline in episodic memory. In symptomatic mutation carriers, cerebral amyloidosis was correlated with worse baseline performance in multiple cognitive composites and predicted greater decline over time in global cognition, working memory, and Mini-Mental State Examination. CONCLUSIONS: Cerebral amyloidosis predicts longitudinal episodic memory decline in presymptomatic ADAD and multidomain cognitive decline in symptomatic ADAD. These findings imply that amyloidosis in the brain is an indicator of early cognitive decline and provides a useful outcome measure for early assessment and prevention treatment trials.Item Change in Cerebrospinal Fluid Tau Microtubule Binding Region Detects Symptom Onset, Cognitive Decline, Tangles, and Atrophy in Dominantly Inherited Alzheimer's Disease(Wiley, 2023) Horie, Kanta; Li, Yan; Barthélemy, Nicolas R.; Gordon, Brian; Hassenstab, Jason; Benzinger, Tammie L. S.; Fagan, Anne M.; Morris, John C.; Karch, Celeste M.; Xiong, Chengjie; Allegri, Ricardo; Mendez, Patricio Chrem; Ikeuchi, Takeshi; Kasuga, Kensaku; Noble, James; Farlow, Martin; Chhatwal, Jasmeer; Day, Gregory; Schofield, Peter R.; Masters, Colin L.; Levin, Johannes; Jucker, Mathias; Lee, Jae-Hong; Roh, Jee Hoon; Sato, Chihiro; Sachdev, Pallavi; Koyama, Akihiko; Reyderman, Larisa; Bateman, Randall J.; McDade, Eric; Dominantly Inherited Alzheimer Network; Neurology, School of MedicineObjective: Identifying cerebrospinal fluid measures of the microtubule binding region of tau (MTBR-tau) species that reflect tau aggregation could provide fluid biomarkers that track Alzheimer's disease related neurofibrillary tau pathological changes. We examined the cerebrospinal fluid (CSF) MTBR-tau species in dominantly inherited Alzheimer's disease (DIAD) mutation carriers to assess the association with Alzheimer's disease (AD) biomarkers and clinical symptoms. Methods: Cross-sectional and longitudinal CSF from 229 DIAD mutation carriers and 130 mutation non-carriers had sequential characterization of N-terminal/mid-domain phosphorylated tau (p-tau) followed by MTBR-tau species and tau positron emission tomography (tau PET), other soluble tau and amyloid biomarkers, comprehensive clinical and cognitive assessments, and brain magnetic resonance imaging of atrophy. Results: CSF MTBR-tau species located within the putative "border" region and one species corresponding to the "core" region of aggregates in neurofibrillary tangles (NFTs) increased during the presymptomatic stage and decreased during the symptomatic stage. The "border" MTBR-tau species were associated with amyloid pathology and CSF p-tau; whereas the "core" MTBR-tau species were associated stronger with tau PET and CSF measures of neurodegeneration. The ratio of the border to the core species provided a continuous measure of increasing amounts that tracked clinical progression and NFTs. Interpretation: Changes in CSF soluble MTBR-tau species preceded the onset of dementia, tau tangle increase, and atrophy in DIAD. The ratio of 4R-specific MTBR-tau (border) to the NFT (core) MTBR-tau species corresponds to the pathology of NFTs in DIAD and change with disease progression. The dynamics between different MTBR-tau species in the CSF may serve as a marker of tau-related disease progression and target engagement of anti-tau therapeutics.Item Characterisation of age and polarity at onset in bipolar disorder(Cambridge University Press, 2021-12) Kalman, Janos L.; Olde Loohuis, Loes M.; Vreeker, Annabel; McQuillin, Andrew; Stahl, Eli A.; Ruderfer, Douglas; Grigoroiu-Serbanescu, Maria; Panagiotaropoulou, Georgia; Ripke, Stephan; Bigdeli, Tim B.; Stein, Frederike; Meller, Tina; Meinert, Susanne; Pelin, Helena; Streit, Fabian; Papiol, Sergi; Adams, Mark J.; Adolfsson, Rolf; Adorjan, Kristina; Agartz, Ingrid; Aminoff, Sofie R.; Anderson-Schmidt, Heike; Andreassen, Ole A.; Ardau, Raffaella; Aubry, Jean-Michel; Balaban, Ceylan; Bass, Nicholas; Baune, Bernhard T.; Bellivier, Frank; Benabarre, Antoni; Bengesser, Susanne; Berrettini, Wade H.; Boks, Marco P.; Bromet, Evelyn J.; Brosch, Katharina; Budde, Monika; Byerley, William; Cervantes, Pablo; Chillotti, Catina; Cichon, Sven; Clark, Scott R.; Comes, Ashley L.; Corvin, Aiden; Coryell, William; Craddock, Nick; Craig, David W.; Croarkin, Paul E.; Cruceanu, Cristiana; Czerski, Piotr M.; Dalkner, Nina; Dannlowski, Udo; Degenhardt, Franziska; Del Zompo, Maria; DePaulo, J. Raymond; Djurovic, Srdjan; Edenberg, Howard J.; Al Eissa, Mariam; Elvsåshagen, Torbjørn; Etain, Bruno; Fanous, Ayman H.; Fellendorf, Frederike; Fiorentino, Alessia; Forstner, Andreas J.; Frye, Mark A.; Fullerton, Janice M.; Gade, Katrin; Garnham, Julie; Gershon, Elliot; Gill, Michael; Goes, Fernando S.; Gordon-Smith, Katherine; Grof, Paul; Guzman-Parra, Jose; Hahn, Tim; Hasler, Roland; Heilbronner, Maria; Heilbronner, Urs; Jamain, Stephane; Jimenez, Esther; Jones, Ian; Jones, Lisa; Jonsson, Lina; Kahn, Rene S.; Kelsoe, John R.; Kennedy, James L.; Kircher, Tilo; Kirov, George; Kittel-Schneider, Sarah; Klöhn-Saghatolislam, Farah; Knowles, James A.; Kranz, Thorsten M.; Lagerberg, Trine Vik; Landen, Mikael; Lawson, William B.; Leboyer, Marion; Li, Qingqin S.; Maj, Mario; Malaspina, Dolores; Manchia, Mirko; Mayoral, Fermin; McElroy, Susan L.; McInnis, Melvin G.; McIntosh, Andrew M.; Medeiros, Helena; Melle, Ingrid; Milanova, Vihra; Mitchell, Philip B.; Monteleone, Palmiero; Monteleone, Alessio Maria; Nöthen, Markus M.; Novak, Tomas; Nurnberger, John I.; O'Brien, Niamh; O'Connell, Kevin S.; O'Donovan, Claire; O'Donovan, Michael C.; Opel, Nils; Ortiz, Abigail; Owen, Michael J.; Pålsson, Erik; Pato, Carlos; Pato, Michele T.; Pawlak, Joanna; Pfarr, Julia-Katharina; Pisanu, Claudia; Potash, James B.; Rapaport, Mark H.; Reich-Erkelenz, Daniela; Reif, Andreas; Reininghaus, Eva; Repple, Jonathan; Richard-Lepouriel, Hélène; Rietschel, Marcella; Ringwald, Kai; Roberts, Gloria; Rouleau, Guy; Schaupp, Sabrina; Scheftner, William A.; Schmitt, Simon; Schofield, Peter R.; Schubert, K. Oliver; Schulte, Eva C.; Schweizer, Barbara; Senner, Fanny; Severino, Giovanni; Sharp, Sally; Slaney, Claire; Smeland, Olav B.; Sobell, Janet L.; Squassina, Alessio; Stopkova, Pavla; Strauss, John; Tortorella, Alfonso; Turecki, Gustavo; Twarowska-Hauser, Joanna; Veldic, Marin; Vieta, Eduard; Vincent, John B.; Xu, Wei; Zai, Clement C.; Zandi, Peter P.; Psychiatric Genomics Consortium (PGC) Bipolar Disorder Working Group; International Consortium on Lithium Genetics (ConLiGen); Colombia-US Cross Disorder Collaboration in Psychiatric Genetics; Di Florio, Arianna; Smoller, Jordan W.; Biernacka, Joanna M.; McMahon, Francis J.; Alda, Martin; Müller-Myhsok, Bertram; Koutsouleris, Nikolaos; Falkai, Peter; Freimer, Nelson B.; Andlauer, Till F.M.; Schulze, Thomas G.; Ophoff, Roel A.; Biochemistry and Molecular Biology, School of MedicineBackground: Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools. Aims: To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics. Method: Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts. Results: Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = -0.34 years, s.e. = 0.08), major depression (β = -0.34 years, s.e. = 0.08), schizophrenia (β = -0.39 years, s.e. = 0.08), and educational attainment (β = -0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO. Conclusions: AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.