Abstract
We searched for genetic causes of major psychiatric disorders (bipolar disorder, schizoaffective disorder, and schizophrenia) in a large, densely affected pedigree from Northern Sweden that originated with three pairs of founders born around 1650. We applied a systematic genomic approach to the pedigree via karyotyping (N = 9), genome-wide SNP arrays (N = 418), whole-exome sequencing (N = 26), and whole-genome sequencing (N = 10). Comprehensive analysis did not identify plausible variants of strong effect. Rather, pedigree cases had significantly higher genetic risk scores compared to pedigree and community controls.
Highlights
IntroductionThe genetic basis of major psychiatric disorders (i.e., bipolar disorder, schizoaffective disorder, and schizophrenia) has been intensively investigated over the past decade atop of substantial efforts dating to 1980s1
The genetic basis of major psychiatric disorders has been intensively investigated over the past decade atop of substantial efforts dating to 1980s1
Common variant analyses We evaluated whether selected genomic regions could be linked to GWAS results for bipolar disorder[21] or schizophrenia[22] using partitioned LD score regression23,24. pLDSC is an extension of LD score regression allowing estimation of whether a set of genomic regions are enriched for the SNP-heritability of a trait based on GWAS summary statistics
Summary
The genetic basis of major psychiatric disorders (i.e., bipolar disorder, schizoaffective disorder, and schizophrenia) has been intensively investigated over the past decade atop of substantial efforts dating to 1980s1. Most of the implicated findings to date have been for common genetic variants[1,2,3,4], with significant common-variant genetic correlations between these disorders[5] These results are unquestionably informative[6], they usually implicate broad genomic regions with imprecise connections to particular genes. Dense pedigrees can result from high commonvariant genetic burden[7], they can be explained by rare variation of strong effect inherited from common ancestors. Systematic searches of such pedigrees are a complementary strategy to attempt to identify genetic variants of strong effect
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