Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Germany; Department of Psychiatry and Psychotherapy, University Hospital Munich, Germany; and International Max Planck Research School for Translational Psychiatry, Germany.
Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, USA.
Br J Psychiatry. 2021 Dec;219(6):659-669. doi: 10.1192/bjp.2021.102.
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.
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
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.
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.
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.
研究双相情感障碍发病年龄（AAO）和发病极性（PAO）的表型和遗传特征，可以为疾病病理提供新的见解，并有助于开发筛查工具。
检查 AAO 和 PAO 的遗传结构及其与双相情感障碍疾病特征的关联。
对来自 34 个队列和一个复制样本（n=2237）的双相情感障碍患者进行 AAO（n=12977）和 PAO（n=6773）的全基因组关联研究（GWAS）和多基因评分（PGS）分析。在其中两个队列中研究了发病与疾病特征的关联。
较早的 AAO 与出现精神病症状、自杀意念、较低的教育程度、不住在一起和较少发作的可能性更高相关。抑郁发作与自杀意念相关，而躁狂发作与妄想和躁狂发作相关。观察到 AAO 在队列和起源大陆之间存在系统差异。这也反映在基于单核苷酸变异的遗传力估计中，更严格的发病定义具有更高的遗传力。自闭症谱系障碍（β=-0.34 岁，s.e.=0.08）、重度抑郁症（β=-0.34 岁，s.e.=0.08）、精神分裂症（β=-0.39 岁，s.e.=0.08）和教育程度（β=-0.31 岁，s.e.=0.08）的 PGS 增加与 AAO 较早相关。AAO GWAS 确定了一个显著的位置，但这一发现没有复制。GWAS 和 PGS 分析均未与 PAO 产生显著关联。
AAO 和 PAO 与双相情感障碍严重程度的指标相关。发病较早的个体表现出对广泛精神疾病特征的多基因易感性增加。队列、大陆和表型定义之间 AAO 的系统差异引入了显著的异质性，影响了分析。
