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PubMed · 42687878

Genomic dimensions deconstruct the clinical heterogeneity of bipolar disorder.

Tracey van der Veen·Markos Tesfaye·Jessica Mei Kay Yang·Toni Boltz·Friederike S David·Shane Crinion·Maria Koromina·Till F M Andlauer·Tim B Bigdeli·Brandon J Coombes·Tiffany A Greenwood·Georgia Panagiotaropoulou·Nadine Parker·Heejong Sung·Nicholas Bass·Jonathan R I Coleman·José Guzman-Parra·Janos L Kalman·Caroline C McGrouther·Brittany L Mitchell·Aaditya V Rangan·Katie Scott·Alexey Shadrin·Daniel J Smith·Annabel Vreeker·Kristina Adorjan·Diego Albani·Silvia Alemany·Ney Alliey-Rodriguez·Anastasia Antoniou·Michael Bauer·Eva C Beins·Marco P Boks·Rosa Bosch·Ben M Brumpton·Nathalie Brunkhorst-Kanaan·Monika Budde·William Byerley·Judit Cabana-Domínguez·Murray J Cairns·Bernardo Carpiniello·Miquel Casas·Pablo Cervantes·Chris Chatzinakos·Toni-Kim Clarke·Isabelle Claus·Cristiana Cruceanu·Alfredo Cuellar-Barboza·Piotr M Czerski·Konstantinos Dafnas·Anders M Dale·Nina Dalkner·J Raymond DePaulo·Franziska Degenhardt·Srdjan Djurovic·Valentina Escott-Price·Ayman H Fanous·Frederike T Fellendorf·I Nicol Ferrier·Liz Forty·Josef Frank·Oleksandr Frei·Nelson B Freimer·Julie Garnham·Ian R Gizer·Scott D Gordon·Katherine Gordon-Smith·Tim Hahn·Marian L Hamshere·Arvid Harder·Martin Hautzinger·Urs Heilbronner·Dennis Hellgren·Stefan Herms·Ian B Hickie·Per Hoffmann·Peter A Holmans·Stéphane Jamain·Lina Jonsson·James L Kennedy·Sarah Kittel-Schneider·James A Knowles·Elise Koch·Manolis Kogevinas·Thorsten M Kranz·Steven A Kushner·Catharina Lavebratt·Jacob Lawrence·Markus Leber·Penelope A Lind·Susanne Lucae·Martin Lundberg·Donald J MacIntyre·Wolfgang Maier·Adam X Maihofer·Dolores Malaspina·Mirko Manchia·Eirini Maratou·Lina Martinsson·Melvin G McInnis
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Abstract

Bipolar disorder's (BD) clinical heterogeneity has an unresolved genetic basis. We meta-analyzed genome-wide association studies (GWAS) of 16 BD subphenotypes in 226,032 individuals from 57 cohorts (38,022 cases); 10 advanced to multivariate and multi-trait analyses. Four factors (compulsive, psychotic, dysregulated, internalizing) explained 82.8% of shared genetic variance. BD1 and BD2 loaded on distinct factors despite a high genetic correlation; 87.0% of common-factor loci were significant in neither subtype. Unipolar mania aligned with psychosis over internalizing, and was distinguishable from BD1, and rapid cycling showed heritable cross-domain liability. We identified 356 risk loci, 158 novel, including the first univariate-GWAS associations for psychosis, unipolar mania, rapid cycling and schizoaffective disorder-and 249 credible genes (89 high-confidence), 12 with approved-drug or clinical-phase annotations. Cell-type association showed a midbrain dopaminergic-GABAergic gradient along the psychotic factor. BD's genetic architecture appears hierarchical-a general liability resolving into dimensions of course and comorbidity, beyond subtypes.

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Tracey van der Veen, Markos Tesfaye, Jessica Mei Kay Yang, Toni Boltz, Friederike S David, Shane Crinion, Maria Koromina, Till F M Andlauer, Tim B Bigdeli, Brandon J Coombes, Tiffany A Greenwood, Georgia Panagiotaropoulou, Nadine Parker, Heejong Sung, Nicholas Bass, Jonathan R I Coleman, José Guzman-Parra, Janos L Kalman, Caroline C McGrouther, Brittany L Mitchell, Aaditya V Rangan, Katie Scott, Alexey Shadrin, Daniel J Smith, Annabel Vreeker, Kristina Adorjan, Diego Albani, Silvia Alemany, Ney Alliey-Rodriguez, Anastasia Antoniou, Michael Bauer, Eva C Beins, Marco P Boks, Rosa Bosch, Ben M Brumpton, Nathalie Brunkhorst-Kanaan, Monika Budde, William Byerley, Judit Cabana-Domínguez, Murray J Cairns, Bernardo Carpiniello, Miquel Casas, Pablo Cervantes, Chris Chatzinakos, Toni-Kim Clarke, Isabelle Claus, Cristiana Cruceanu, Alfredo Cuellar-Barboza, Piotr M Czerski, Konstantinos Dafnas, Anders M Dale, Nina Dalkner, J Raymond DePaulo, Franziska Degenhardt, Srdjan Djurovic, Valentina Escott-Price, Ayman H Fanous, Frederike T Fellendorf, I Nicol Ferrier, Liz Forty, Josef Frank, Oleksandr Frei, Nelson B Freimer, Julie Garnham, Ian R Gizer, Scott D Gordon, Katherine Gordon-Smith, Tim Hahn, Marian L Hamshere, Arvid Harder, Martin Hautzinger, Urs Heilbronner, Dennis Hellgren, Stefan Herms, Ian B Hickie, Per Hoffmann, Peter A Holmans, Stéphane Jamain, Lina Jonsson, James L Kennedy, Sarah Kittel-Schneider, James A Knowles, Elise Koch, Manolis Kogevinas, Thorsten M Kranz, Steven A Kushner, Catharina Lavebratt, Jacob Lawrence, Markus Leber, Penelope A Lind, Susanne Lucae, Martin Lundberg, Donald J MacIntyre, Wolfgang Maier, Adam X Maihofer, Dolores Malaspina, Mirko Manchia, Eirini Maratou, Lina Martinsson, Melvin G McInnis. 2026-08-26. Genomic dimensions deconstruct the clinical heterogeneity of bipolar disorder.. https://doi.org/10.21203/rs.3.rs-10041361%2Fv1

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Effectiveness of high-dose versus standard-dose influenza vaccines against hospitalisation according to frailty risk: a prespecified analysis of the randomised trial DANFLU-2.

BACKGROUND: Frailty is a major risk factor for influenza-related complications and can influence vaccine effectiveness. We aimed to assess the relative vaccine effectiveness (rVE) of high-dose (HD-IIV) versus standard-dose inactivated influenza vaccine (SD-IIV) in older adults aged 65 years or older according to frailty risk. METHODS: This study was a prespecified analysis of DANFLU-2, an open-label, individually randomised trial, conducted in Denmark during three consecutive influenza seasons (2022-23, 2023-24, and 2024-25). Adults aged 65 years or older were randomised (1:1) to the HD-IIV or SD-IIV group. The primary endpoint was hospitalisation for influenza or pneumonia. Frailty was defined according to the validated Hospital Frailty Risk Score (HFRS) based on ICD-10 codes within 10 years before randomisation. Participants were stratified into three HFRS categories, namely low (<5 points), intermediate (5-15 points), and high (>15 points) frailty risk. The rVE of HD-IIV versus SD-IIV against the primary endpoint was assessed across prespecified HFRS categories and treating HFRS as a continuous variable. Pearson's chi-square test was used to compare safety events across frailty risk groups and randomisation groups. FINDINGS: Among 332&#x2009;438 randomised participants (mean age 73&#xb7;7 years [SD 5&#xb7;8]; 161&#x2009;538 [48&#xb7;6%] were female), 276&#x2009;173 (83&#xb7;1%) had low frailty risk, 52&#x2009;395 (15&#xb7;8%) had intermediate frailty risk, and 3861 (1&#xb7;2%) had high frailty risk. The primary endpoint of hospitalisation for influenza or pneumonia occurred in 1424 (0&#xb7;5%) of 276&#x2009;173 participants with low frailty risk, 761 (1&#xb7;5%) of 52&#x2009;395 with intermediate frailty risk, and 163 (4&#xb7;2%) of 3861 with high frailty risk (relative risk [RR] for intermediate vs low frailty risk 2&#xb7;8 [95% CI 2&#xb7;6-3&#xb7;1]; RR for high vs low frailty risk 8&#xb7;2 [7&#xb7;0-9&#xb7;6]). HFRS as a continuous variable significantly modified the effect of HD-IIV versus SD-IIV against the primary endpoint with higher rVE estimates with increasing HFRS (pinteraction=0&#xb7;020). The rVE was 0&#xb7;2% (95% CI -10&#xb7;8 to 10&#xb7;2) among those with low frailty risk, 13&#xb7;1% (-0&#xb7;4 to 24&#xb7;8) among those with intermediate frailty risk, and 19&#xb7;9% (-10&#xb7;3 to 42&#xb7;1) among those with high frailty risk. No significant interaction was observed when HFRS was assessed according to the prespecified categorical frailty groups (pinteraction=0&#xb7;17). The proportion of participants with at least one serious adverse event increased across frailty risk groups (13&#x2009;366 [4&#xb7;8%] of 275&#x2009;795 for low frailty risk, 5475 [10&#xb7;5%] of 52&#x2009;315 for intermediate frailty risk, and 777 [20&#xb7;2%] of 3850 for high frailty risk; p<0&#xb7;0001), with similar proportions of serious adverse events in the HD-IIV and SD-IIV groups for each frailty risk group. INTERPRETATION: Among adults aged 65 years or older in Denmark, frailty risk might modify the effects of HD-IIV versus SD-IIV against hospitalisation for influenza or pneumonia, with higher rVE estimates with increasing frailty risk. These findings might support considering high-dose influenza vaccines for frail older adults. However, effect modification was not evident when frailty was assessed using prespecified categorical subgroups, and subgroup-specific estimates were imprecise, with 95% CIs crossing the null. These results should be considered exploratory, warranting further investigation. FUNDING: The DANFLU-2 trial was funded by Sanofi.

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