Parent-of-origin effects and cross-disorder transmission in familial psychiatric risk: A nationwide study of 1.77 million offspring.
While familial aggregation of severe mental disorders (SMD)-schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD)-is established, parent-of-origin effects and specific parental diagnostic pairings influencing offspring neurodevelopmental disorders (NDDs) and SMD risk remain unclear.
Using Taiwan's National Health Insurance Research Database, 1,770,192 singleton offspring and parents (1980-2000 births) were classified into sixteen parental SMD combinations. Outcomes included ASD, ADHD, SCZ, BD, and MDD. Logistic regression estimated adjusted odds ratios.
Parental SMD increased all offspring risks with distinct parent-of-origin and cross-disorder effects. ASD risk rose from 0.3% (unaffected families) to 1.6% with dual parental SCZ (OR = 7.11 [2.24-22.51]), highest when paternal SCZ co-occurred with maternal MDD (OR = 5.99 [3.28-10.93]). ADHD prevalence (1.8% reference) peaked with paternal MDD plus maternal BD (OR = 3.88 [2.87-5.26]). SCZ risk reached 5.2% with dual parental SCZ (OR = 14.03 [7.30-26.99]), with strongest cross-disorder effect for paternal SCZ plus maternal BD (OR = 21.69 [7.65-61.50]). BD showed pronounced concordant transmission (both parents BD, OR = 31.86 [17.56-57.79]) and substantial cross-risk with paternal BD plus maternal MDD (OR = 12.97 [8.60-19.54]). MDD demonstrated dose-response associations with dual parental MDD (OR = 4.56 [4.17-4.98]) and additional risks observed in paternal MDD plus maternal BD (OR = 5.19 [3.91-6.88]).
This large cohort highlights complex patterns of concordant and cross-disorder psychiatric risk aggregation with distinct parent-of-origin effects. While these findings demonstrate strong clinical associations, they underscore the need for early monitoring in high-risk families rather than establishing definitive causal pathways.
Using Taiwan's National Health Insurance Research Database, 1,770,192 singleton offspring and parents (1980-2000 births) were classified into sixteen parental SMD combinations. Outcomes included ASD, ADHD, SCZ, BD, and MDD. Logistic regression estimated adjusted odds ratios.
Parental SMD increased all offspring risks with distinct parent-of-origin and cross-disorder effects. ASD risk rose from 0.3% (unaffected families) to 1.6% with dual parental SCZ (OR = 7.11 [2.24-22.51]), highest when paternal SCZ co-occurred with maternal MDD (OR = 5.99 [3.28-10.93]). ADHD prevalence (1.8% reference) peaked with paternal MDD plus maternal BD (OR = 3.88 [2.87-5.26]). SCZ risk reached 5.2% with dual parental SCZ (OR = 14.03 [7.30-26.99]), with strongest cross-disorder effect for paternal SCZ plus maternal BD (OR = 21.69 [7.65-61.50]). BD showed pronounced concordant transmission (both parents BD, OR = 31.86 [17.56-57.79]) and substantial cross-risk with paternal BD plus maternal MDD (OR = 12.97 [8.60-19.54]). MDD demonstrated dose-response associations with dual parental MDD (OR = 4.56 [4.17-4.98]) and additional risks observed in paternal MDD plus maternal BD (OR = 5.19 [3.91-6.88]).
This large cohort highlights complex patterns of concordant and cross-disorder psychiatric risk aggregation with distinct parent-of-origin effects. While these findings demonstrate strong clinical associations, they underscore the need for early monitoring in high-risk families rather than establishing definitive causal pathways.
Authors
Yeh Yeh, Hsu Hsu, Tsai Tsai, Bai Bai, Su Su, Chen Chen, Liang Liang, Chen Chen, Hsu Hsu
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