Polygenic overlap and shared genetic loci between loneliness, severe mental disorders, and cardiovascular disease risk factors suggest shared molecular mechanisms

Rødevand, Linn; Bahrami, Shahram; Frei, Oleksandr; Lin, Aihua; Shadrin, Alexey; Smeland, Olav B.; O’Connell, Kevin; Elvsåshagen, Torbjørn; Winterton, Adriano; Quintana, Daniel; Hindley, Guy; Werner, Maren Caroline Frogner; Djurovic, Srdjan; Dale, Anders M.; Lagerberg, Trine Vik; Steen, Nils Eiel; Andreassen, Ole A.

doi:10.1038/s41398-020-01142-4

Cited by 41 publications

(33 citation statements)

References 79 publications

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“…P -values are corrected for inflation using a genomic inflation control procedure [ 12 , 28 ]. Consistent with previous publications [ 12 , 24 , 31 , 32 ], we used the thresholds condFDR<0.01 and conjFDR<0.05. For further information, see Supplementary Methods and method review [ 28 ].…”

Section: Methodsmentioning

confidence: 99%

Extensive bidirectional genetic overlap between bipolar disorder and cardiovascular disease phenotypes

et al. 2021

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Patients with bipolar disorder (BIP) have a high risk of cardiovascular disease (CVD), despite considerable individual variation. The mechanisms underlying comorbid CVD in BIP remain largely unknown. We investigated polygenic overlap between BIP and CVD phenotypes, including CVD risk factors and coronary artery disease (CAD). We analyzed large genome-wide association studies of BIP (n = 51,710) and CVD phenotypes (n = 159,208–795,640), using bivariate causal mixture model (MiXeR), which estimates the total amount of shared genetic variants, and conjunctional false discovery rate (FDR), which identifies specific overlapping loci. MiXeR revealed polygenic overlap between BIP and body mass index (BMI) (82%), diastolic and systolic blood pressure (20–22%) and CAD (11%) despite insignificant genetic correlations. Using conjunctional FDR < 0.05, we identified 129 shared loci between BIP and CVD phenotypes, mainly BMI (n = 69), systolic (n = 53), and diastolic (n = 53) blood pressure, of which 22 are novel BIP loci. There was a pattern of mixed effect directions of the shared loci between BIP and CVD phenotypes. Functional analyses indicated that the shared loci are linked to brain-expressed genes and involved in neurodevelopment, lipid metabolism, chromatin assembly/disassembly and intracellular processes. Altogether, the study revealed extensive polygenic overlap between BIP and comorbid CVD, implicating shared molecular genetic mechanisms. The mixed effect directions of the shared loci suggest variation in genetic susceptibility to CVD across BIP subgroups, which may underlie the heterogeneity of CVD comorbidity in BIP patients. The findings suggest more focus on targeted lifestyle interventions and personalized pharmacological treatment to reduce CVD comorbidity in BIP.

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Section: Methodsmentioning

confidence: 99%

Extensive bidirectional genetic overlap between bipolar disorder and cardiovascular disease phenotypes

et al. 2021

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“…For instance, the heritability of loneliness is 40–50% [65]. We recently revealed several loneliness risk loci shared with SMDs and CVD risk factors with mainly concordant effect directions [18 ▪ ]. The findings suggest that people with SMDs, especially major depression, may have an inherent propensity to loneliness, which in turn was associated with an increased genetic risk of CVD [18 ▪ ].…”

Section: Shared Genetic Mechanismsmentioning

confidence: 99%

“…We recently revealed several loneliness risk loci shared with SMDs and CVD risk factors with mainly concordant effect directions [18 ▪ ]. The findings suggest that people with SMDs, especially major depression, may have an inherent propensity to loneliness, which in turn was associated with an increased genetic risk of CVD [18 ▪ ]. Together with the evidence of a genetic overlap between SMDs and CVD [15,16,17 ▪ ,60], the results suggest overlapping genetic loci between loneliness, SMDs and CVD risk factors, which may underlie part of the clinical relationship between loneliness, SMDs and CVD comorbidity [18 ▪ ].…”

Section: Shared Genetic Mechanismsmentioning

confidence: 99%

“…Recent findings have shed new light on this relation [12 ▪ ]. Furthermore, increasing evidence highlights the importance of loneliness in the comorbidity [13,14], and genetic overlap is discovered [15,16,17 ▪ ,18 ▪ ]. The aim of this review is to provide an update on the prevalence of CVD morbidity and mortality among people with SMDs compared with the general population, and present new findings into the role of socioeconomic, psychosocial and genetic factors in the CVD comorbidity.…”

Section: Introductionmentioning

confidence: 99%

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Cardiovascular disease risk in people with severe mental disorders: an update and call for action

Rødevand

Tesli

Andreassen

2022

Current Opinion in Psychiatry

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Purpose of reviewCardiovascular disease (CVD) is a major cause of premature death in people with severe mental disorders (SMDs). This review provides an update on the level of CVD mortality and morbidity, as well as the socioeconomic, psychosocial and genetic factors associated with the comorbidity, and offer directions for improved interventions to reduce CVD in SMDs.Recent findingsThe level of CVD mortality and morbidity has sustained high in people with SMDs during the past decades, but the causal mechanism must be further elucidated. Psychosocial and socioeconomic challenges are frequent in SMDs as well as in CVD. Further, recent studies have revealed genetic variants jointly associated with SMDs, CVD risk and social factors. These findings highlight the need for more targeted interventions, prediction tools and psychosocial approaches to comorbid CVD in SMDs.SummaryThe level of CVD comorbidity remains high in SMDs, indicating that most people with SMDs have not benefitted from recent medical advances. A complex interplay between genetic and social vulnerability to CVD, which differs across subgroups of patients, seems to be involved. Further research is required to meet the urgent need for earlier, more efficient intervention approaches and preventive strategies for comorbid CVD in SMD.

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“…BPDS is characterized by disabling mood states reflected in manic or hypomanic episodes ( e.g., elevated, expansive, or irritable mood, and hyperactivity; American Psychiatric Association, 2013; Charney et al, 2020), depressive episodes (e.g., low mood or loss of interest or pleasure), as well as mixed mood episodes (Kraepelin, 1921;Swann et al, 2013) and/or chronic affective instability . BPDS is associated with high rates of disability (World Health Organization, 2001), medical comorbidities (Fiedorowicz et al, 2009;Rødevand et al, 2021;Rowland & Marwaha, 2018) and suicidality (Kozloff et al, 2010). Hypomania is a sub-manic state characterized by elevated and sometimes irritable mood, and can be measured along a continuum of experiences using self-report questionnaires (Hoyle et al, 2015).…”

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confidence: 99%

Positive moods are all alike? Differential affect amplification effects of ‘elated’ versus ‘calm’ mental im-agery in young adults reporting hypomanic-like experiences

Vannucci¹,

Bonsall²,

Simplicio³

et al. 2021

Preprint

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Positive mood amplification is a hallmark of the bipolar disorder spectrum (BPDS). We need bet-ter understanding of cognitive mechanisms leading to such elevated mood. Generation of vivid, emo-tionally compelling mental imagery is proposed to act as an ‘emotional amplifier’ in BPDS.We used a positive mental imagery generation paradigm to manipulate affect in a subclinical BPDS-relevant sample reporting high (n=31) vs. low (n=30) hypomanic-like experiences on the Mood Dis-order Questionnaire (MDQ). Participants were randomized to an ‘elated’ or ‘calm’ mental imagery condi-tion, rating their momentary affect four times across the experimental session. We hypothesized greater affect increase in the high (vs. low) MDQ group assigned to the elated (vs. calm) imagery generation condition. We further hypothesized that this change would be driven by increases in the types of affect typically associated with (hypo)mania, i.e., suggestive of high activity lev-els.Mixed model and time-series analysis showed that for the high MDQ group, affect increased steeply and in a sustained manner over time in the ‘elated’ imagery condition, and more shallowly in ‘calm’. The low-MDQ group did not show this amplification effect. Analysis of affect clusters showed high-MDQ mood amplification in the ‘elated’ imagery condition was most pronounced for active affective states. This experimental model of BPDS-relevant mood amplification shows evidence that positive men-tal imagery drives changes in affect in the high MDQ group in a targeted manner. Findings inform cogni-tive mechanisms of mood amplification, and spotlight prevention strategies targeting elated imagery, while potentially retaining calm imagery to preserve adaptive positive emotionality.

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Polygenic overlap and shared genetic loci between loneliness, severe mental disorders, and cardiovascular disease risk factors suggest shared molecular mechanisms

Cited by 41 publications

References 79 publications

Extensive bidirectional genetic overlap between bipolar disorder and cardiovascular disease phenotypes

Extensive bidirectional genetic overlap between bipolar disorder and cardiovascular disease phenotypes

Cardiovascular disease risk in people with severe mental disorders: an update and call for action

Positive moods are all alike? Differential affect amplification effects of ‘elated’ versus ‘calm’ mental im-agery in young adults reporting hypomanic-like experiences

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