Risk and protective factors for mental disorders beyond genetics: an evidence‐based atlas

Abstract

Decades of research have revealed numerous risk factors for mental disorders beyond genetics, but their consistency and magnitude remain uncer tain. We conducted a "metaumbrella" systematic synthesis of umbrella reviews, which are systematic reviews of metaanalyses of individual studies, by searching international databases from inception to January 1, 2021. We included umbrella reviews on nonpurely genetic risk or protective factors for any ICD/DSM mental disorders, applying an established classification of the credibility of the evidence: class I (convinc ing), class II (highly suggestive), class III (suggestive), class IV (weak). Sensitivity analyses were conducted on prospective studies to test for temporality (reverse causation), TRANSD criteria were applied to test transdiagnosticity of factors, and A Measurement Tool to Assess Systematic Reviews (AMSTAR) was employed to address the quality of metaanalyses. Fourteen eligible umbrella reviews were retrieved, summarizing 390 metaanalyses and 1,180 associations between putative risk or protective factors and mental disorders. We included 176 class I to III evidence associations, relating to 142 risk/protective factors. The most robust risk factors (class I or II, from prospective designs) were 21. For dementia, they included type 2 diabetes mellitus (risk ratio, RR from 1.54 to 2.28), depression (RR from 1.65 to 1.99) and low frequency of social con tacts (RR=1.57). For opioid use disorders, the most robust risk factor was tobacco smoking (odds ratio, OR=3.07). For nonorganic psychotic disorders, the most robust risk factors were clinical high risk state for psychosis (OR=9.32), cannabis use (OR=3.90), and childhood adversities (OR=2.80). For depressive disorders, they were widowhood (RR=5.59), sexual dysfunction (OR=2.71), three (OR=1.99) or fourfive (OR=2.06) metabolic factors, childhood physical (OR=1.98) and sexual (OR=2.42) abuse, job strain (OR=1.77), obesity (OR=1.35), and sleep disturbances (RR=1.92). For autism spectrum disorder, the most robust risk factor was maternal overweight pre/during pregnancy (RR=1.28). For attention deficit/hyperactivity disorder (ADHD), they were maternal prepregnancy obesity (OR=1.63), maternal smoking during pregnancy (OR=1.60), and maternal overweight pre/during pregnancy (OR=1.28). Only one robust protective factor was detected: high physical activity (hazard ratio, HR=0.62) for Alzheimer's disease. In all, 32.9% of the associations were of high quality, 48.9% of medium quality, and 18.2% of low quality. Transdiagnostic class IIII risk/protective factors were mostly involved in the early neurodevelopmental period. The evidencebased atlas of key risk and protective factors identified in this study represents a benchmark for advancing clinical characterization and research, and for expand ing early intervention and preventive strategies for mental disorders.

Primary Psychosis: Risk and Protective Factors and Early Detection of the Onset

“…Regarding parental factors, one of the most studied factors is parental age at the time of the birth of the children with a higher risk of developing primary psychosis in the offspring for maternal age <20 years or >30 years and a further risk for women with >35 years of age [23]. Similar associations were found for paternal age <20 years [15,23] and >35 years [23,24], with evidence of an increased risk for >45-years-old fathers [15]. Other parental factors associated with an increased o risk of developing primary psychosis are maternal pre-pregnancy obesity [15] or hypertension [23] and having more than three previous pregnancies [23], and low paternal socio-economic status [13,15].…”

“…The season of birth is an additional important factor affecting the risk of psychosis [13]. In particular, winter season of birth [20,23] and winter/spring season of birth in Northern hemisphere [15,23,24] have been found to be strongly associated with an increased risk of developing primary psychosis. This risk appears to become stronger with the increase of latitude and the severity of winter [20].…”

“…Ethnicity represents one of the most implicated variables in the onset of primary psychosis. The concept of ethnicity includes two dimensions: having an immigrant status and belonging to a specific ethnic minority [15,24]. Both of these aspects may be better defined as risk markers as they may be the result of different interacting risk factors (e.g., racism, minority stress, isolation, low economic status etc.).…”

“…Both of these aspects may be better defined as risk markers as they may be the result of different interacting risk factors (e.g., racism, minority stress, isolation, low economic status etc.). In particular, the migrant status itself contributes to the pathogenesis of psychosis [13,15,20,24], mostly in secondgeneration immigrants [15,24]. For instance, being a Black-Caribbean ethnicity in England has the strongest statistical association [15,24], while other minorities like North African immigrants in Europe [15,24] and Black African and Asian ethnicity in England [15] showed weaker evidence.…”

“…In particular, the migrant status itself contributes to the pathogenesis of psychosis [13,15,20,24], mostly in secondgeneration immigrants [15,24]. For instance, being a Black-Caribbean ethnicity in England has the strongest statistical association [15,24], while other minorities like North African immigrants in Europe [15,24] and Black African and Asian ethnicity in England [15] showed weaker evidence. Different studies showed that migrants with black skin color might share a common risk exposure, possibly because of a genetic vulnerability background or for factors connected to ethnic disadvantage and lower socioeconomic status [25].…”