1 Introduction
Bipolar disorder (BD) is a recurrent mental disorder with unclear etiology, often causing severe disability among people who suffer from it (Kessing et al., 2017). Despite evidence that bipolar disorder is highly heritable(Sandstrom et al., 2019; YANG et al., 2018), the specific pathogenic mechanism involving a complex combination of genetic and external environmental variables remains unknown(Breuer et al., 2018). Endophenotypes are disease-related signatures that are strongly heritable and independent of the patient’s clinical condition(McGue. et al., 2017). Detecting the endophenotype of bipolar disorder can provide us with important information about the etiology of this complicated disease, as well as a useful target for early diagnosis, prevention, and individualized therapy. Working as an endophenotype requires meeting certain requirements, such as disease-related, state independence, familial association, and co-segregation within families, according to prior studies(Gottesman. et al., 2003). Several studies have found that bipolar disorder patients suffer cognitive abnormalities, particularly in sustained attention, verbal learning, and executive functioning(Douglas et al., 2017; Van Rheenen et al., 2017; Luperdi et al., 2021; Ceylan et al.,2020).
These cognitive deficiencies are more noticeable during the disease’s exacerbation phase, but recent discoveries have indicated that patients still exhibit chronic cognitive impairment following symptom remission, albeit to a smaller extent than during the exacerbation period (Cardenas et al., 2016). The endurance of these abnormalities suggests that they may be a defining feature of the condition rather than merely a symptom of its start. Furthermore, if the cognitive deficiencies of a bipolar patient’s unaffected first-degree relative manifest as an intermediate condition, i.e., less severe than the patient but more severe than the healthy control, the cognitive deficits are most likely an underlying endophenotype of bipolar disorder. The endophenotypes linked with cognitive deficits in bipolar disorder are contentious, with some research proposing that verbal memory deficits(Rodriguez et al., 2012; Kulkarni et al., 2010), executive function deficits, and selective attention deficits were endophenotypes of cognitive deficits in bipolar disorder(Normala et al., 2012; Bauer et al., 2016). There was, however, research that contradicts these findings (Daban et al., 2016). For example, except for the ability to recognize surprising facial expressions, cognitive deficiencies did not fit the features of the bipolar illness endophenotype in a study of 172 individuals with bipolar disorder in remission and 52 first-degree relatives of patients without the disorder(Kjaerstad et al., 2020). Exploratory investigations on the endophenotypes linked with cognitive deficits in bipolar disorder are still relevant due to the disparity in the results of earlier studies. Furthermore, the majority of prior studies used Caucasians as the study sample, and there are few studies on domestic Han Chinese.
Neurological soft signs (NSS) are small neurological abnormalities in motor coordination, sensory integration, and disinhibition. These defects are associated with changes in cortical and subcortical structures in patients with mental disorders, which can be objectively stimulated and effectively evaluated(Ciufolini et al., 2018; Rathod et al., 2020). NSS in mental diseases partly reflects the developmental abnormalities of the nervous system caused by genetic and non-genetic processes(Nasab et al., 2017). 20 The majority of recent studies on psychiatric diseases’ neurological soft signals have used schizophrenia patients as the study sample(Yingying et al., 2020; Yingying et al., 2017). The aberrant neurodevelopmental theory of schizophrenia is supported by increased NSS(Bora et al., 2015), and some items in the NSS have been identified as probable endophenotypes of schizophrenia(Yingying et al., 2020; Yingying et al., 2017). Patients with bipolar disorder, for example, displayed much more motor coordination and sensory integration symptoms than healthy controls, according to case-control research(Sagheer et al., 2018). Additionally, patients with bipolar disorder experienced much more NSS than healthy controls, per the results of a 2018 meta-analysis(Bora et al., 2018). However, when opposed to the literature on schizophrenia, NSS in bipolar disorder is a comparatively understudied area. Numerous studies, on the other hand, have discovered significant neurological and genetic similarities between schizophrenia and bipolar disorder(Bora et al., 2016; Gotra et al., 2020; Chrobak et al., 2021). As a result, it’s acceptable to assume that, similar to schizophrenia, several items in the NSS fit the requirements for a bipolar disorder endophenotype. Given that both cognitive deficits and NSS are associated with neurodevelopmental problems in psychiatric disorders, combining the two endophenotypes of the disorder may result in a more effective endophenotype. Because numerous risk variables for psychiatric disorders frequently cluster together to represent a genetic risk for the same disorder, it has been suggested that these risk factors be combined to create a composite or multivariate endophenotype to better identify genetic risk(Turetsky et al., 2007).
The goal of this study was twofold: first, to find cognitive deficits and NSS-related items that met the endophenotypic criteria for bipolar disorder by assessing cognitive function and NSS in euthymic patients with bipolar disorder (EBP), their unaffected first-degree relatives (FDR), and healthy controls (HC); and second, to see if a composite endophenotype of bipolar disorder can be created using cognitive deficiencies and NSS items that meet endophenotypic criteria and verify it.