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Genetic risk scores and family history as predictors of schizophrenia in Nordic registers

Published online by Cambridge University Press:  25 September 2017

Y. Lu ,
J. G. Pouget ,
O. A. Andreassen ,
S. Djurovic ,
T. Esko ,
C. M. Hultman ,
A. Metspalu ,
L. Milani ,
T. Werge  and
P. F. Sullivan
Y. Lu
Affiliation:
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-17177 Stockholm, Sweden
J. G. Pouget
Affiliation:
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
O. A. Andreassen
Affiliation:
NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, 0424 Oslo, Norway
S. Djurovic
Affiliation:
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway Department of Clinical Science, NORMENT, KG Jebsen Centre for Psychosis Research, University of Bergen, Bergen, Norway
T. Esko
Affiliation:
Estonian Genome Center, University of Tartu, Tartu, Estonia
C. M. Hultman
Affiliation:
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-17177 Stockholm, Sweden
A. Metspalu
Affiliation:
Estonian Genome Center, University of Tartu, Tartu, Estonia
L. Milani
Affiliation:
Estonian Genome Center, University of Tartu, Tartu, Estonia
T. Werge
Affiliation:
The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Denmark Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
P. F. Sullivan*
Affiliation:
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-17177 Stockholm, Sweden Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, NC, 27599-7264, USA
*
Author for correspondence: P. F. Sullivan, E-mail: [email protected]
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Abstract

Background

Family history is a long-standing and readily obtainable risk factor for schizophrenia (SCZ). Low-cost genotyping technologies have enabled large genetic studies of SCZ, and the results suggest the utility of genetic risk scores (GRS, direct assessments of inherited common variant risk). Few studies have evaluated family history and GRS simultaneously to ask whether one can explain away the other.

Methods

We studied 5959 SCZ cases and 8717 controls from four Nordic countries. All subjects had family history data from national registers and genome-wide genotypes that were processed through the quality control procedures used by the Psychiatric Genomics Consortium. Using external training data, GRS were estimated for SCZ, bipolar disorder (BIP), major depression, autism, educational attainment, and body mass index. Multivariable modeling was used to estimate effect sizes.

Results

Using harmonized genomic and national register data from Denmark, Estonia, Norway, and Sweden, we confirmed that family history of SCZ and GRS for SCZ and BIP were risk factors for SCZ. In a joint model, the effects of GRS for SCZ and BIP were essentially unchanged, and the effect of family history was attenuated but remained significant. The predictive capacity of a model including GRS and family history neared the minimum for clinical utility.

Conclusions

Combining national register data with measured genetic risk factors represents an important investigative approach for psychotic disorders. Our findings suggest the potential clinical utility of combining GRS and family history for early prediction and diagnostic improvements.

Keywords

Family historygenetic risk scoregenome-wide associationGWASschizophrenia
Type
Original Articles
Information
Psychological Medicine , Volume 48 , Issue 7 , May 2018 , pp. 1201 - 1208
Copyright
Copyright © Cambridge University Press 2017 

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