Heterogeneity analysis provides evidence for a genetically homogeneous subtype of bipolar-disorder.
<h4>Background</h4>Bipolar Disorder (BD) is a complex disease. It is heterogeneous, both at the phenotypic and genetic level, although the extent and impact of this heterogeneity is not fully understood. One way to assess this heterogeneity is to look for patterns in the subphenotype dat...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2025-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0314288 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1823861072730259456 |
|---|---|
| author | Caroline C McGrouther Aaditya V Rangan Arianna Di Florio Jeremy A Elman Nicholas J Schork John Kelsoe Bipolar Disorder Working Group of the Psychiatric Genomics Consortium |
| author_facet | Caroline C McGrouther Aaditya V Rangan Arianna Di Florio Jeremy A Elman Nicholas J Schork John Kelsoe Bipolar Disorder Working Group of the Psychiatric Genomics Consortium |
| author_sort | Caroline C McGrouther |
| collection | DOAJ |
| description | <h4>Background</h4>Bipolar Disorder (BD) is a complex disease. It is heterogeneous, both at the phenotypic and genetic level, although the extent and impact of this heterogeneity is not fully understood. One way to assess this heterogeneity is to look for patterns in the subphenotype data. Because of the variability in how phenotypic data was collected by the various BD studies over the years, homogenizing this subphenotypic data is a challenging task, and so is replication. An alternative methodology, taken here, is to set aside the intricacies of subphenotype and allow the genetic data itself to determine which subjects define a homogeneous genetic subgroup (termed 'bicluster' below).<h4>Results</h4>In this paper, we leverage recent advances in heterogeneity analysis to look for genetically-driven subgroups (i.e., biclusters) within the broad phenotype of Bipolar Disorder. We first apply this covariate-corrected biclustering algorithm to a cohort of 2524 BD cases and 4106 controls from the Bipolar Disease Research Network (BDRN) within the Psychiatric Genomics Consortium (PGC). We find evidence of genetic heterogeneity delineating a statistically significant bicluster comprising a subset of BD cases which exhibits a disease-specific pattern of differential-expression across a subset of SNPs. This disease-specific genetic pattern (i.e., 'genetic subgroup') replicates across the remaining data-sets collected by the PGC containing 5781/8289, 3581/7591, and 6825/9752 cases/controls, respectively. This genetic subgroup (discovered without using any BD subtype information) was more prevalent in Bipolar type-I than in Bipolar type-II.<h4>Conclusions</h4>Our methodology has successfully identified a replicable homogeneous genetic subgroup of bipolar disorder. This subgroup may represent a collection of correlated genetic risk-factors for BDI. By investigating the subgroup's bicluster-informed polygenic-risk-scoring (PRS), we find that the disease-specific pattern highlighted by the bicluster can be leveraged to eliminate noise from our GWAS analyses and improve risk prediction. This improvement is particularly notable when using only a relatively small subset of the available SNPs, implying improved SNP replication. Though our primary focus is only the analysis of disease-related signal, we also identify replicable control-related heterogeneity. |
| format | Article |
| id | doaj-art-f5b8ee16afe746339577a62431381b08 |
| institution | Kabale University |
| issn | 1932-6203 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-f5b8ee16afe746339577a62431381b082025-02-10T05:30:39ZengPublic Library of Science (PLoS)PLoS ONE1932-62032025-01-01201e031428810.1371/journal.pone.0314288Heterogeneity analysis provides evidence for a genetically homogeneous subtype of bipolar-disorder.Caroline C McGroutherAaditya V RanganArianna Di FlorioJeremy A ElmanNicholas J SchorkJohn KelsoeBipolar Disorder Working Group of the Psychiatric Genomics Consortium<h4>Background</h4>Bipolar Disorder (BD) is a complex disease. It is heterogeneous, both at the phenotypic and genetic level, although the extent and impact of this heterogeneity is not fully understood. One way to assess this heterogeneity is to look for patterns in the subphenotype data. Because of the variability in how phenotypic data was collected by the various BD studies over the years, homogenizing this subphenotypic data is a challenging task, and so is replication. An alternative methodology, taken here, is to set aside the intricacies of subphenotype and allow the genetic data itself to determine which subjects define a homogeneous genetic subgroup (termed 'bicluster' below).<h4>Results</h4>In this paper, we leverage recent advances in heterogeneity analysis to look for genetically-driven subgroups (i.e., biclusters) within the broad phenotype of Bipolar Disorder. We first apply this covariate-corrected biclustering algorithm to a cohort of 2524 BD cases and 4106 controls from the Bipolar Disease Research Network (BDRN) within the Psychiatric Genomics Consortium (PGC). We find evidence of genetic heterogeneity delineating a statistically significant bicluster comprising a subset of BD cases which exhibits a disease-specific pattern of differential-expression across a subset of SNPs. This disease-specific genetic pattern (i.e., 'genetic subgroup') replicates across the remaining data-sets collected by the PGC containing 5781/8289, 3581/7591, and 6825/9752 cases/controls, respectively. This genetic subgroup (discovered without using any BD subtype information) was more prevalent in Bipolar type-I than in Bipolar type-II.<h4>Conclusions</h4>Our methodology has successfully identified a replicable homogeneous genetic subgroup of bipolar disorder. This subgroup may represent a collection of correlated genetic risk-factors for BDI. By investigating the subgroup's bicluster-informed polygenic-risk-scoring (PRS), we find that the disease-specific pattern highlighted by the bicluster can be leveraged to eliminate noise from our GWAS analyses and improve risk prediction. This improvement is particularly notable when using only a relatively small subset of the available SNPs, implying improved SNP replication. Though our primary focus is only the analysis of disease-related signal, we also identify replicable control-related heterogeneity.https://doi.org/10.1371/journal.pone.0314288 |
| spellingShingle | Caroline C McGrouther Aaditya V Rangan Arianna Di Florio Jeremy A Elman Nicholas J Schork John Kelsoe Bipolar Disorder Working Group of the Psychiatric Genomics Consortium Heterogeneity analysis provides evidence for a genetically homogeneous subtype of bipolar-disorder. PLoS ONE |
| title | Heterogeneity analysis provides evidence for a genetically homogeneous subtype of bipolar-disorder. |
| title_full | Heterogeneity analysis provides evidence for a genetically homogeneous subtype of bipolar-disorder. |
| title_fullStr | Heterogeneity analysis provides evidence for a genetically homogeneous subtype of bipolar-disorder. |
| title_full_unstemmed | Heterogeneity analysis provides evidence for a genetically homogeneous subtype of bipolar-disorder. |
| title_short | Heterogeneity analysis provides evidence for a genetically homogeneous subtype of bipolar-disorder. |
| title_sort | heterogeneity analysis provides evidence for a genetically homogeneous subtype of bipolar disorder |
| url | https://doi.org/10.1371/journal.pone.0314288 |
| work_keys_str_mv | AT carolinecmcgrouther heterogeneityanalysisprovidesevidenceforageneticallyhomogeneoussubtypeofbipolardisorder AT aadityavrangan heterogeneityanalysisprovidesevidenceforageneticallyhomogeneoussubtypeofbipolardisorder AT ariannadiflorio heterogeneityanalysisprovidesevidenceforageneticallyhomogeneoussubtypeofbipolardisorder AT jeremyaelman heterogeneityanalysisprovidesevidenceforageneticallyhomogeneoussubtypeofbipolardisorder AT nicholasjschork heterogeneityanalysisprovidesevidenceforageneticallyhomogeneoussubtypeofbipolardisorder AT johnkelsoe heterogeneityanalysisprovidesevidenceforageneticallyhomogeneoussubtypeofbipolardisorder AT bipolardisorderworkinggroupofthepsychiatricgenomicsconsortium heterogeneityanalysisprovidesevidenceforageneticallyhomogeneoussubtypeofbipolardisorder |