Inga Margret Antonsdottir, Byron Creese, Lambertus Klei, Mary Ann A. DeMichele-Sweet, Elise A. Weamer, Pablo Garcia-Gonzalez, Marta Marquie, Mercè Boada, Emilio Alarcón-Martín, Sergi Valero, NIA-LOAD Family Based Study Consortium, Alzheimer's Disease Genetics Consortium (ADGC), AddNeuroMed Consortium, Yushi Liu, Basavaraj Hooli, Dag Aarsland, Geir Selbaek, Sverre Bergh, Arvid Rongve, Ingvild Saltvedt, Håvard K. Skjellegrind, Bo Engdahl, Ole A. Andreassen, Barbara Borroni, Patrizia Mecocci, Yehani Wedatilake, Richard Mayeux, Tatiana Foroud, Agustín Ruiz, Oscar L. Lopez, M. Ilyas Kamboh, Clive Ballard, Bernie Devlin, Constantine Lyketsos, Robert A. Sweet
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Sweet","doi":"10.1002/trc2.12472","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> INTRODUCTION</h3>\n \n <p>Individuals with Alzheimer's disease (AD) commonly experience neuropsychiatric symptoms of psychosis (AD+P) and/or affective disturbance (depression, anxiety, and/or irritability, AD+A). This study's goal was to identify the genetic architecture of AD+P and AD+A, as well as their genetically correlated phenotypes.</p>\n </section>\n \n <section>\n \n <h3> METHODS</h3>\n \n <p>Genome-wide association meta-analysis of 9988 AD participants from six source studies with participants characterized for AD+P AD+A, and a joint phenotype (AD+A+P).</p>\n </section>\n \n <section>\n \n <h3> RESULTS</h3>\n \n <p>AD+P and AD+A were genetically correlated. However, AD+P and AD+A diverged in their genetic correlations with psychiatric phenotypes in individuals without AD. 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引用次数: 0
摘要
导言：阿尔茨海默病（AD）患者通常会出现精神病（AD+P）和/或情感障碍（抑郁、焦虑和/或易怒，AD+A）等神经精神症状。本研究的目标是确定AD+P和AD+A的遗传结构及其与遗传相关的表型：全基因组关联荟萃分析了来自六项研究的9988名AD参与者，这些参与者的特征为AD+P AD+A以及联合表型（AD+A+P）：结果：AD+P和AD+A在遗传上相关。然而，AD+P 和 AD+A 与无 AD 患者精神表型的遗传相关性存在差异。AD+P与双相情感障碍呈负遗传相关，与抑郁症状呈正相关。AD+A与焦虑症呈正相关，与抑郁症状的相关性比AD+P更强。AD+P和AD+A+P具有显著的估计遗传率，而AD+A则没有。对与这三种表型最密切相关的基因位点进行的研究发现了重叠和独特的关联：讨论：AD+P、AD+A和AD+A+P既有共同的遗传关联，也有不同的遗传关联，这表明将遗传学见解纳入未来治疗发展的重要性：众所周知，被诊断为阿尔茨海默病的患者通常合并有精神病和情感症状。在这里，我们首次研究了这一临床观察结果背后的遗传结构，确定阿尔茨海默病的精神病和情感表型与遗传相关。然而，阿尔茨海默病的精神病和情感表型与未患阿尔茨海默病的个体所评估的精神病表型在遗传相关性方面存在差异。阿尔茨海默病的精神病与双相情感障碍呈负遗传相关，与抑郁症状呈正遗传相关，而阿尔茨海默病的情感表型与焦虑症呈正相关，比精神病与抑郁症状的相关性更强。对与精神病、情感或联合表型最密切相关的基因位点进行研究，发现了重叠和独特的关联。
Genetic associations with psychosis and affective disturbance in Alzheimer's disease
INTRODUCTION
Individuals with Alzheimer's disease (AD) commonly experience neuropsychiatric symptoms of psychosis (AD+P) and/or affective disturbance (depression, anxiety, and/or irritability, AD+A). This study's goal was to identify the genetic architecture of AD+P and AD+A, as well as their genetically correlated phenotypes.
METHODS
Genome-wide association meta-analysis of 9988 AD participants from six source studies with participants characterized for AD+P AD+A, and a joint phenotype (AD+A+P).
RESULTS
AD+P and AD+A were genetically correlated. However, AD+P and AD+A diverged in their genetic correlations with psychiatric phenotypes in individuals without AD. AD+P was negatively genetically correlated with bipolar disorder and positively with depressive symptoms. AD+A was positively correlated with anxiety disorder and more strongly correlated than AD+P with depressive symptoms. AD+P and AD+A+P had significant estimated heritability, whereas AD+A did not. Examination of the loci most strongly associated with the three phenotypes revealed overlapping and unique associations.
DISCUSSION
AD+P, AD+A, and AD+A+P have both shared and divergent genetic associations pointing to the importance of incorporating genetic insights into future treatment development.
Highlights
It has long been known that psychotic and affective symptoms are often comorbid in individuals diagnosed with Alzheimer's disease. Here we examined for the first time the genetic architecture underlying this clinical observation, determining that psychotic and affective phenotypes in Alzheimer's disease are genetically correlated.
Nevertheless, psychotic and affective phenotypes in Alzheimer's disease diverged in their genetic correlations with psychiatric phenotypes assessed in individuals without Alzheimer's disease. Psychosis in Alzheimer's disease was negatively genetically correlated with bipolar disorder and positively with depressive symptoms, whereas the affective phenotypes in Alzheimer's disease were positively correlated with anxiety disorder and more strongly correlated than psychosis with depressive symptoms.
Psychosis in Alzheimer's disease, and the joint psychotic and affective phenotype, had significant estimated heritability, whereas the affective in AD did not.
Examination of the loci most strongly associated with the psychotic, affective, or joint phenotypes revealed overlapping and unique associations.
期刊介绍：
Alzheimer''s & Dementia: Translational Research & Clinical Interventions (TRCI) is a peer-reviewed, open access,journal from the Alzheimer''s Association®. The journal seeks to bridge the full scope of explorations between basic research on drug discovery and clinical studies, validating putative therapies for aging-related chronic brain conditions that affect cognition, motor functions, and other behavioral or clinical symptoms associated with all forms dementia and Alzheimer''s disease. The journal will publish findings from diverse domains of research and disciplines to accelerate the conversion of abstract facts into practical knowledge: specifically, to translate what is learned at the bench into bedside applications. The journal seeks to publish articles that go beyond a singular emphasis on either basic drug discovery research or clinical research. Rather, an important theme of articles will be the linkages between and among the various discrete steps in the complex continuum of therapy development. For rapid communication among a multidisciplinary research audience involving the range of therapeutic interventions, TRCI will consider only original contributions that include feature length research articles, systematic reviews, meta-analyses, brief reports, narrative reviews, commentaries, letters, perspectives, and research news that would advance wide range of interventions to ameliorate symptoms or alter the progression of chronic neurocognitive disorders such as dementia and Alzheimer''s disease. The journal will publish on topics related to medicine, geriatrics, neuroscience, neurophysiology, neurology, psychiatry, clinical psychology, bioinformatics, pharmaco-genetics, regulatory issues, health economics, pharmacoeconomics, and public health policy as these apply to preclinical and clinical research on therapeutics.
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