Evaluating the Impact of Nonrandom Mating: Psychiatric Outcomes Among the Offspring of Pairs Diagnosed With Schizophrenia and Bipolar Disorder

Abstract

BACKGROUND: Nonrandom mating has been shown for psychiatric diagnoses, with hypothesized-but not quantified-implications for offspring liability. This national cohort study enumerated the incidence of major psychiatric disorders among the offspring of parent pairs affected with schizophrenia (SCZ) and/or bipolar disorder (BIP) (i.e., dual-affected pairs). METHODS: Participants were all Swedish residents alive or born between 1968 and 2013 (n = 4,255,196 unique pairs and 8,343,951 offspring). Offspring with dual-affected, single-affected, and unaffected parents were followed (1973-2013) for incidence of broad psychiatric disorders. Primary outcomes included hazard ratio (HR) and cumulative incidence for SCZ and BIP in the offspring. Additional outcomes included any neuropsychiatric, anxiety, depressive, personality, or substance use disorders. Cumulative incidences of SCZ and BIP were used to inform heritability models for these disorders. RESULTS: Hazards were highest within disorder (e.g., offspring of dual-SCZ pairs had sharply raised hazards for SCZ [HR = 55.3]); however, they were significantly raised for all diagnoses (HR range = 2.89-11.84). Incidences were significantly higher for the majority of outcomes, with 43.4% to 48.5% diagnosed with "any" disorder over followup. Risks were retained, with modest attenuations, for the offspring of heterotypic pairs. The estimated heritability of liability for SCZ (h 2 = 0.62, 95% confidence interval = 0.55-0.70) and BIP (h 2 = 0.52, 95% confidence interval = 0.46-0.58) did not differ significantly from estimates derived from single-affected parents. CONCLUSIONS: Risks for a broad spectrum of psychiatric diagnoses are significantly raised in the offspring of dualaffected parents, in line with expectations from a polygenic model of liability to disease risk. How these risks may contribute to population maintenance of these disorders is considered.

Integrative analysis of genome-wide association studies identifies novel loci associated with neuropsychiatric disorders

“…Each of these five neuropsychiatric disorders is highly heritable, with heritability estimates in twin studies ranging from 40 to 88% [13][14][15][16][17][18][19][20] , and a number of genome-wide significant (GWS) loci have been identified from large scale genome-wide association studies (GWASs), especially through the collective effort of the Psychiatric Genomics Consortium (PGC). Among the five neuropsychiatric disorders, SCZ has been best studied with 200 GWS loci identified as summarized in the GWAS catalog 21,22 , whereas the number of GWS loci for MDD and BIP are somewhat less with 44 and 30 discovered loci, respectively, based on recent studies 23,24 .…”

One versus two biological parents with mental disorders: Relationship to educational attainment in the next generation

“…Regarding mechanisms of these effects, previous work has demonstrated uniquely high risks for psychiatric difficulties in the offspring of parents who are both affected with major psychiatric illness. Children of parents dual-affected with schizophrenia or bipolar disorder have, for example, been shown in both Danish and Swedish national samples (Gottesman et al, 2010 ; Nordsletten et al, 2020 ) to have substantially increased lifetime risks for these conditions (18–27% for schizophrenia; 19–25% for bipolar disorder), rising to a minimum of 43% (up to a maximum 67%) for any major psychiatric disorder. Similar to the patterns seen here for education, these risks appear largely retained regardless of which parent is affected with a given disorder and, indeed, whether parents differ in their respective diagnosis (Nordsletten et al, 2020 ).…”

“…Children of parents dual-affected with schizophrenia or bipolar disorder have, for example, been shown in both Danish and Swedish national samples (Gottesman et al, 2010 ; Nordsletten et al, 2020 ) to have substantially increased lifetime risks for these conditions (18–27% for schizophrenia; 19–25% for bipolar disorder), rising to a minimum of 43% (up to a maximum 67%) for any major psychiatric disorder. Similar to the patterns seen here for education, these risks appear largely retained regardless of which parent is affected with a given disorder and, indeed, whether parents differ in their respective diagnosis (Nordsletten et al, 2020 ). Our present findings, which controlled for offspring's own diagnostic status, indicate that the relationship between parental mental health and offspring educational outcomes extends meaningfully beyond the clinic, impacting core, functional domains regardless of the presence of a psychiatric condition.…”

“…In addition, the focus of extant work on the distinct investigation of mothers or fathers – as opposed to mothers and fathers – fails to reflect findings showing that individuals with psychiatric conditions often partner together (Nordsletten et al, 2016 ). The offspring of families where both parents have a psychiatric disorder have remarkably high rates of psychiatric disorders themselves (Gottesman, Laursen, Bertelsen, & Mortensen, 2010 ; Nordsletten et al, 2020 ), which in turn may have additionally negative impacts on educational attainment, presumably through a combination of both genetic and environmental adversities. Given findings suggesting unique impacts of maternal and paternal psychopathology on offspring development and related outcomes – including academic achievement (Harter, 2000 ) – understanding whether, and to what degree, the differences manifest additively in dual-affected families presents an important question, as it may help identify a particularly vulnerable group of individuals in need of early support and intervention.…”

Assortative mating and parental genetic relatedness drive the pathogenicity of variably expressive variants

“…These complexities necessitate examining other factors, such as parental phenotype and genotype, in affected probands that may elucidate their ultimate phenotypic trajectory. Previous reports have shown that family history is a risk factor for neurodevelopmental disorders, with increased within and cross-disorder risk observed among relatives of individuals with psychiatric disease [17][18][19] . This increase in liability towards multiple diagnostic outcomes may be due to the overlapping genetic etiologies of neurodevelopmental disorders 20 and is particularly relevant for understanding mechanisms of variable expressivity of rare variants.…”