Bivariate causal mixture model quantifies polygenic overlap between complex traits beyond genetic correlation

Oleksandr Frei; Dominic Holland; Olav B Smeland; Alexey A Shadrin; Chun Chieh Fan; Steffen Maeland; Kevin S O'Connell; Yunpeng Wang; Srdjan Djurovic; Wesley K Thompson; Ole A Andreassen; Anders M Dale

doi:10.1038/s41467-019-10310-0

Bivariate causal mixture model quantifies polygenic overlap between complex traits beyond genetic correlation

Nat Commun. 2019 Jun 3;10(1):2417. doi: 10.1038/s41467-019-10310-0.

Authors

Oleksandr Frei¹, Dominic Holland^{2

3}, Olav B Smeland^{4

5}, Alexey A Shadrin⁴, Chun Chieh Fan^{2

6

7}, Steffen Maeland⁴, Kevin S O'Connell⁴, Yunpeng Wang^{4

2

7}, Srdjan Djurovic^{8

9}, Wesley K Thompson^{10

11}, Ole A Andreassen^{4

5}, Anders M Dale^{12

13

14

15}

Affiliations

¹ NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, 0424, Oslo, Norway. oleksandr.frei@gmail.com.
² Center for Multimodal Imaging and Genetics, University of California at San Diego, La Jolla, CA, 92037, USA.
³ Department of Neurosciences, University of California, San Diego, La Jolla, CA, 92093, USA.
⁴ NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, 0424, Oslo, Norway.
⁵ Division of Mental Health and Addiction, Oslo University Hospital, 0407, Oslo, Norway.
⁶ Department of Cognitive Sciences, University of California at San Diego, La Jolla, CA, 92093, USA.
⁷ Department of Radiology, University of California, San Diego, La Jolla, CA, 92093, USA.
⁸ Department of Medical Genetics, Oslo University Hospital, 0424, Oslo, Norway.
⁹ NORMENT, KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, 5020, Bergen, Norway.
¹⁰ Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, CA, 92093, USA.
¹¹ Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Capital Region of Denmark, Roskilde, 4000, Denmark.
¹² Center for Multimodal Imaging and Genetics, University of California at San Diego, La Jolla, CA, 92037, USA. andersmdale@gmail.com.
¹³ Department of Neurosciences, University of California, San Diego, La Jolla, CA, 92093, USA. andersmdale@gmail.com.
¹⁴ Department of Radiology, University of California, San Diego, La Jolla, CA, 92093, USA. andersmdale@gmail.com.
¹⁵ Department of Psychiatry, University of California, San Diego, La Jolla, CA, 92093, USA. andersmdale@gmail.com.

Abstract

Accumulating evidence from genome wide association studies (GWAS) suggests an abundance of shared genetic influences among complex human traits and disorders, such as mental disorders. Here we introduce a statistical tool, MiXeR, which quantifies polygenic overlap irrespective of genetic correlation, using GWAS summary statistics. MiXeR results are presented as a Venn diagram of unique and shared polygenic components across traits. At 90% of SNP-heritability explained for each phenotype, MiXeR estimates that 8.3 K variants causally influence schizophrenia and 6.4 K influence bipolar disorder. Among these variants, 6.2 K are shared between the disorders, which have a high genetic correlation. Further, MiXeR uncovers polygenic overlap between schizophrenia and educational attainment. Despite a genetic correlation close to zero, the phenotypes share 8.3 K causal variants, while 2.5 K additional variants influence only educational attainment. By considering the polygenicity, discoverability and heritability of complex phenotypes, MiXeR analysis may improve our understanding of cross-trait genetic architectures.

Publication types

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

MeSH terms

Bipolar Disorder / genetics*
Gene Frequency
Genome-Wide Association Study
Humans
Linkage Disequilibrium
Models, Genetic*
Models, Statistical*
Multifactorial Inheritance*
Schizophrenia / genetics*

Abstract

Publication types

MeSH terms

Grants and funding