Disentangling the influences of parental genetics on offspring's cognition, education, and psychopathology via genetic and phenotypic pathways

Luiza K Axelrud; Maurício S Hoffmann; Daniel E Vosberg; Marcos Santoro; Pedro M Pan; Ary Gadelha; Sintia I Belangero; Euripedes C Miguel; Jean Shin; Anita Thapar; Jordan W Smoller; Zdenka Pausova; Luis A Rohde; Matthew C Keller; Tomáš Paus; Giovanni A Salum

doi:10.1111/jcpp.13708

Disentangling the influences of parental genetics on offspring's cognition, education, and psychopathology via genetic and phenotypic pathways

J Child Psychol Psychiatry. 2023 Mar;64(3):408-416. doi: 10.1111/jcpp.13708. Epub 2022 Sep 26.

Authors

Luiza K Axelrud^{1

2}, Maurício S Hoffmann^{1

2

3

4}, Daniel E Vosberg^{5

6}, Marcos Santoro^{2

7

8}, Pedro M Pan^{2

8}, Ary Gadelha^{2

8}, Sintia I Belangero^{2

7

8}, Euripedes C Miguel^{2

9}, Jean Shin^{5

10

11

12}, Anita Thapar¹³, Jordan W Smoller¹⁴, Zdenka Pausova^{5

10

11

12

15}, Luis A Rohde^{1

2

16}, Matthew C Keller¹⁷, Tomáš Paus^{6

15

18

19

20

21}, Giovanni A Salum^{1

2}

Affiliations

¹ Section on Negative Affect and Social Processes, Department of Psychiatry and Legal Medicine, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
² National Institute of Developmental Psychiatry (INPD, CNPq), São Paulo, Brazil.
³ Department of Neuropsychiatry, Universidade Federal de Santa Maria (UFSM), Santa Maria, Brazil.
⁴ Care Policy and Evaluation Centre, London School of Economics and Political Science, London, UK.
⁵ Research Institute, Hospital for Sick Children, Toronto, ON, Canada.
⁶ Centre Hospitalier Universitaire Sainte-Justine, University of Montreal, Montreal, QC, Canada.
⁷ Department of Morphology and Genetics, Universidade Federal de São Paulo, São Paulo, Brazil.
⁸ Department of Psychiatry, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil.
⁹ Universidade de São Paulo (USP), São Paulo, Brazil.
¹⁰ Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
¹¹ Department of Physiology, University of Toronto, Toronto, ON, Canada.
¹² Department of Nutritional Sciences, University of Toronto, Toronto, ON, Canada.
¹³ Division of Psychological Medicine and Clinical Neurosciences and MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
¹⁴ Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹⁵ ECOGENE-21, Chicoutimi, QC, Canada.
¹⁶ ADHD Outpatient Program, Department of Psychiatry, Clinical Research Center, Hospital de Clínicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
¹⁷ Department of Microbiology, New York University School of Medicine, New York, NY, USA.
¹⁸ Department of Psychology, University of Toronto, Toronto, ON, Canada.
¹⁹ Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
²⁰ Department of Psychiatry, Faculty of Medicine, University of Montreal, Montreal, QC, Canada.
²¹ Department of Neuroscience, Faculty of Medicine, University of Montreal, Montreal, QC, Canada.

PMID: 36162806
DOI: 10.1111/jcpp.13708

Abstract

Background: Specific pathways of intergenerational transmission of behavioral traits remain unclear. Here, we aim to investigate how parental genetics influence offspring cognition, educational attainment, and psychopathology in youth.

Methods: Participants for the discovery sample were 2,189 offspring (aged 6-14 years), 1898 mothers and 1,017 fathers who underwent genotyping, psychiatric, and cognitive assessments. We calculated polygenic scores (PGS) for cognition, educational attainment, attention-deficit hyperactivity disorder (ADHD), and schizophrenia for the trios. Phenotypes studied included educational and cognitive measures, ADHD and psychotic symptoms. We used a stepwise approach and multiple mediation models to analyze the effect of parental PGS on offspring traits via offspring PGS and parental phenotype. Significant results were replicated in a sample of 1,029 adolescents, 363 mothers, and 307 fathers.

Results: Maternal and paternal PGS for cognition influenced offspring general intelligence and executive function via offspring PGS (genetic pathway) and parental education (phenotypic pathway). Similar results were found for parental PGS for educational attainment and offspring reading and writing skills. These pathways fully explained associations between parental PGS and offspring phenotypes, without residual direct association. Associations with maternal, but not paternal, PGS were replicated. No associations were found between parental PGS for psychopathology and offspring specific symptoms.

Conclusions: Our findings indicate that parental genetics influences offspring cognition and educational attainment by genetic and phenotypic pathways, suggesting the expression of parental phenotypes partially explain the association between parental genetic risk and offspring outcomes. Multiple mediations might represent an effective approach to disentangle distinct pathways for intergenerational transmission of behavioral traits.

Keywords: Genetics; cognition; educational attainment; gene-environment correlation; intergenerational transmission; polygenic scores.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Attention Deficit Disorder with Hyperactivity* / genetics
Cognition
Educational Status
Female
Humans
Mothers
Parents*
Phenotype

Grants and funding

R01MH120482/US National Institute of Mental Health