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{"title"=>"Genome-wide association study in bipolar patients stratified by co-morbidity", "type"=>"journal", "authors"=>[{"first_name"=>"Berit", "last_name"=>"Kerner", "scopus_author_id"=>"7006062229"}, {"first_name"=>"Christophe G.", "last_name"=>"Lambert", "scopus_author_id"=>"36840107900"}, {"first_name"=>"Bengt O.", "last_name"=>"Muthén", "scopus_author_id"=>"7003555242"}], "year"=>2011, "source"=>"PLoS ONE", "identifiers"=>{"pui"=>"363120150", "sgr"=>"83755174462", "issn"=>"19326203", "pmid"=>"22205951", "scopus"=>"2-s2.0-83755174462", "doi"=>"10.1371/journal.pone.0028477", "isbn"=>"1932-6203 (Electronic)\\n1932-6203 (Linking)"}, "id"=>"6d12610e-7050-3538-af96-b44f731e797b", "abstract"=>"BACKGROUND Bipolar disorder is a severe psychiatric disorder with high heritability. Co-morbid conditions are common and might define latent subgroups of patients that are more homogeneous with respect to genetic risk factors. METHODOLOGY In the Caucasian GAIN bipolar disorder sample of 1000 cases and 1034 controls, we tested the association of single nucleotide polymorphisms with patient subgroups defined by co-morbidity. RESULTS Bipolar disorder with psychosis and/or substance abuse in the absence of alcohol dependence was associated with the rare variant rs1039002 in the vicinity of the gene phosphodiesterase 10A (PDE10A) on chromosome 6q27 (p = 1.7×10⁻⁸). PDE10A has been implicated in the pathophysiology of psychosis. Antagonists to the encoded protein are currently in clinical testing. Another rare variant, rs12563333 (p = 5.9×10⁻⁸) on chromosome 1q41 close to the MAP/microtubule affinity-regulating kinase 1 (MARK1) gene, approached the genome-wide level of significance in this subgroup. Homozygotes for the minor allele were present in cases and absent in controls. Bipolar disorder with alcohol dependence and other co-morbidities was associated with SNP rs2727943 (p = 3.3×10⁻⁸) on chromosome 3p26.3 located between the genes contactin-4 precursor (BIG-2) and contactin 6 (CNTN6). All three associations were found under the recessive genetic model. Bipolar disorder with low probability of co-morbid conditions did not show significant associations. CONCLUSION Conceptualizing bipolar disorder as a heterogeneous disorder with regard to co-morbid conditions might facilitate the identification of genetic risk alleles. Rare variants might contribute to the susceptibility to bipolar disorder.", "link"=>"http://www.mendeley.com/research/genomewide-association-study-bipolar-patients-stratified-comorbidity-7", "reader_count"=>31, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>3, "Student > Doctoral Student"=>4, "Researcher"=>6, "Student > Ph. D. Student"=>6, "Student > Postgraduate"=>1, "Other"=>5, "Student > Master"=>2, "Student > Bachelor"=>2, "Professor"=>2}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>3, "Student > Doctoral Student"=>4, "Researcher"=>6, "Student > Ph. D. Student"=>6, "Student > Postgraduate"=>1, "Other"=>5, "Student > Master"=>2, "Student > Bachelor"=>2, "Professor"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>3, "Medicine and Dentistry"=>9, "Agricultural and Biological Sciences"=>9, "Neuroscience"=>6, "Psychology"=>3}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>9}, "Neuroscience"=>{"Neuroscience"=>6}, "Psychology"=>{"Psychology"=>3}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>9}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>3}, "Unspecified"=>{"Unspecified"=>1}}, "reader_count_by_country"=>{"Canada"=>1, "Netherlands"=>1, "United Kingdom"=>1, "Germany"=>1, "Spain"=>1}, "group_count"=>4}

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Figshare

• {"files"=>["https://ndownloader.figshare.com/files/700543"], "description"=>"<p>The Manhattan plot demonstrates the results of the genome-wide association analysis using the Latent Class 1 membership probability as phenotype. This subgroup of bipolar disorder patients was characterized by co-morbidity with substance abuse in 43% of individuals. In this group, 24% of individuals had been diagnosed with four or more co-morbid conditions in their lifetime. Alcohol abuse was prevalent in this patient group (52%), followed by substance abuse. Alcohol dependence was absent. Psychotic symptoms were found in 41% of individuals; about half of those had also used illegal substances. The x-axis depicts the position of the SNPs on the chromosomes with each chromosome shaded in a different color. The y-axis shows the −log10 p-value of the correlation trend test. The most significant finding was with the rare SNP rs1039002 on chromosome 6q27 (correlation trend test p = 1.7×10⁻⁸), followed by rs12563333 on chromosome 1q41 (correlation trend test p = 5.9×10⁻⁸). Within the chromosomal region indicated by SNP rs1039002 is the gene phosphodiesterase 10A. This gene has been implicated in the patho-physiology of psychosis in animal models.</p>", "links"=>[], "tags"=>["latent", "recessive"], "article_id"=>370928, "categories"=>["Mental Health"], "users"=>["Berit Kerner", "Christophe G. Lambert", "Bengt O. Muthén"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0028477.g003", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Genome_wide_association_analysis_for_Latent_Class_1_under_the_recessive_model_/370928", "title"=>"Genome-wide association analysis for Latent Class 1 under the recessive model.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-12-21 00:15:28"}
• {"files"=>["https://ndownloader.figshare.com/files/700685"], "description"=>"<p>The Manhattan plot demonstrates the results of the genome-wide association analysis using the Latent Class 2 membership probability as phenotype. This subgroup of bipolar disorder patients was characterized by co-morbidity with alcohol dependence (100%) and substance abuse (80%). Forty-seven percent of individuals in this subgroup carried lifetime diagnoses of four or more co-morbid conditions. The x-axis depicts the position of the SNPs on the chromosomes, each chromosome shaded in a different color. The y-axis shows the −log10 p-value of the correlation trend test. The most significant association with Latent Class 2 membership probability was with SNP rs2727943 on chromosome 3p26.3 (correlation/trend test p = 3.0×10⁻⁸). This common intergenic variant is located between the genes contactin-4 precursor (<i>BIG-2</i>) and contactin 6 (<i>CNTN6</i>). Deletions in this chromosomal region have been previously associated with autism spectrum disorders.</p>", "links"=>[], "tags"=>["latent", "recessive"], "article_id"=>371070, "categories"=>["Mental Health"], "users"=>["Berit Kerner", "Christophe G. Lambert", "Bengt O. Muthén"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0028477.g004", "stats"=>{"downloads"=>2, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Genome_wide_association_analysis_for_Latent_Class_2_under_the_recessive_model_/371070", "title"=>"Genome-wide association analysis for Latent Class 2 under the recessive model.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-12-21 00:17:50"}
• {"files"=>["https://ndownloader.figshare.com/files/700864"], "description"=>"<p>*Two-tailed; LC, Latent Class; SUBA, substance abuse; OCD, obsessive compulsive disorder; PD, panic disorder; SP, social and specific phobia; ED, eating disorder; ADHD, attention-deficit hyperactivity disorder; ALCAB, alcohol abuse; ALCDEP, alcohol dependence; NIC, nicotine dependence; PSYCH, psychotic symptoms (presence of hallucinations and/or delusions).</p>", "links"=>[], "tags"=>["latent", "profiles"], "article_id"=>371244, "categories"=>["Mental Health"], "users"=>["Berit Kerner", "Christophe G. Lambert", "Bengt O. Muthén"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0028477.t003", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Comparison_of_latent_class_profiles_using_odds_ratios_/371244", "title"=>"Comparison of latent class profiles using odds ratios.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-12-21 00:20:44"}
• {"files"=>["https://ndownloader.figshare.com/files/700823"], "description"=>"<p>All estimates were significant with two-tailed P-values<0.001 comparing the probability of endorsing an item versus not endorsing an item. SUBA, substance abuse; OCD, obsessive compulsive disorder; PD, panic disorder; SP, social and specific phobia; ED, eating disorder; ADHD, attention-deficit hyperactivity disorder; ALCAB, alcohol abuse; ALCDEP, alcohol dependence; NIC, nicotine dependence; PSYCH, psychotic symptoms (presence of hallucinations and/or delusions).</p>", "links"=>[], "tags"=>["endorsing", "co-morbid", "latent"], "article_id"=>371208, "categories"=>["Mental Health"], "users"=>["Berit Kerner", "Christophe G. Lambert", "Bengt O. Muthén"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0028477.t002", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Probability_of_endorsing_a_co_morbid_condition_by_latent_class_/371208", "title"=>"Probability of endorsing a co-morbid condition by latent class.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-12-21 00:20:08"}
• {"files"=>["https://ndownloader.figshare.com/files/355788"], "description"=>"<div><h3>Background</h3><p>Bipolar disorder is a severe psychiatric disorder with high heritability. Co-morbid conditions are common and might define latent subgroups of patients that are more homogeneous with respect to genetic risk factors.</p> <h3>Methodology</h3><p>In the Caucasian GAIN bipolar disorder sample of 1000 cases and 1034 controls, we tested the association of single nucleotide polymorphisms with patient subgroups defined by co-morbidity.</p> <h3>Results</h3><p>Bipolar disorder with psychosis and/or substance abuse in the absence of alcohol dependence was associated with the rare variant rs1039002 in the vicinity of the gene phosphodiesterase 10A (<em>PDE10A</em>) on chromosome 6q27 (p = 1.7×10⁻⁸). <em>PDE10A</em> has been implicated in the pathophysiology of psychosis. Antagonists to the encoded protein are currently in clinical testing. Another rare variant, rs12563333 (p = 5.9×10⁻⁸) on chromosome 1q41 close to the MAP/microtubule affinity-regulating kinase 1 (<em>MARK1</em>) gene, approached the genome-wide level of significance in this subgroup. Homozygotes for the minor allele were present in cases and absent in controls. Bipolar disorder with alcohol dependence and other co-morbidities was associated with SNP rs2727943 (p = 3.3×10⁻⁸) on chromosome 3p26.3 located between the genes contactin-4 precursor (<em>BIG-2</em>) and contactin 6 (<em>CNTN6</em>). All three associations were found under the recessive genetic model. Bipolar disorder with low probability of co-morbid conditions did not show significant associations.</p> <h3>Conclusion</h3><p>Conceptualizing bipolar disorder as a heterogeneous disorder with regard to co-morbid conditions might facilitate the identification of genetic risk alleles. Rare variants might contribute to the susceptibility to bipolar disorder.</p> </div>", "links"=>[], "tags"=>["genome-wide", "bipolar", "patients", "stratified", "co-morbidity"], "article_id"=>130307, "categories"=>["Mental Health"], "users"=>["Berit Kerner", "Christophe G. Lambert", "Bengt O. Muthén"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0028477", "stats"=>{"downloads"=>5, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Genome_Wide_Association_Study_in_Bipolar_Patients_Stratified_by_Co_Morbidity/130307", "title"=>"Genome-Wide Association Study in Bipolar Patients Stratified by Co-Morbidity", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-12-21 00:05:07"}
• {"files"=>["https://ndownloader.figshare.com/files/700308"], "description"=>"<p>Co-morbid conditions and psychotic symptoms are common in bipolar disorder. In the GAIN sample of 1000 bipolar patients, substance abuse/dependence was the most prevalent co-morbid condition, followed by alcohol dependence. Nicotine dependence was present in about 25% of individuals. The prevalence of panic disorder was consistent with other reports in the literature <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0028477#pone.0028477-Nurnberger1\" target=\"_blank\">[23]</a>. Attention deficit hyperactivity disorder, obsessive-compulsive disorder and eating disorder were generally rare, present in less than 7% of individuals. As a comparison we used lifetime prevalence rates of psychiatric disorders from the National Comorbidity Survey Replication Study (NCS-R). In this study the evaluation of ADHD was limited to a subsample of individuals age 44 and younger, which might explain the high prevalence rate. Psychotic symptoms, nicotine dependence and eating disorders had not been evaluated in this study. SUBA, substance abuse; ALCDEP, alcohol dependence; PSYCH, psychotic symptoms (presence of hallucinations and/or delusions); NIC, nicotine dependence; PD, panic disorder; SP, social and specific phobia; ALCAB, alcohol abuse; ADHD, attention-deficit hyperactivity disorder; OCD, obsessive compulsive disorder; ED, eating disorder.</p>", "links"=>[], "tags"=>["prevalence", "co-morbid", "conditions", "psychotic", "symptoms", "bipolar", "patients", "compared", "comorbidity", "replication"], "article_id"=>370686, "categories"=>["Mental Health"], "users"=>["Berit Kerner", "Christophe G. Lambert", "Bengt O. Muthén"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0028477.g001", "stats"=>{"downloads"=>2, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Life_time_prevalence_of_co_morbid_conditions_and_psychotic_symptoms_in_bipolar_patients_of_the_GAIN_study_compared_to_lifetime_prevalence_in_the_National_Comorbidity_Survey_Replication_Study_51_/370686", "title"=>"Life-time prevalence of co-morbid conditions and psychotic symptoms in bipolar patients of the GAIN study compared to lifetime prevalence in the National Comorbidity Survey Replication Study [<b>51</b>].", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-12-21 00:11:26"}
• {"files"=>["https://ndownloader.figshare.com/files/700928"], "description"=>"<p>This table gives the SNP phenotype associations that reached or approached the genome-wide level of significance (after correction for multiple testing using the Bonferroni method). The position of the SNPs on the chromosomes is given in base pairs according to the Ensemble database, assembly GRCh37.p2, Feb 2009, Version 60.37e. SNP, single nucleotide polymorphism; LC1, Latent Class 1; LC2, Latent Class 2, Chr., chromosome; Corr P, p-value of the correlation-trend test, Bonf. P, Bonferroni corrected p-value.</p>", "links"=>[], "tags"=>["genome-wide", "analyses", "latent"], "article_id"=>371311, "categories"=>["Mental Health"], "users"=>["Berit Kerner", "Christophe G. Lambert", "Bengt O. Muthén"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0028477.t005", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Results_of_genome_wide_case_control_association_analyses_using_latent_class_membership_as_phenotype_/371311", "title"=>"Results of genome-wide case control association analyses using latent class membership as phenotype.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-12-21 00:21:51"}
• {"files"=>["https://ndownloader.figshare.com/files/700894"], "description"=>"<p>Co-occurrence of co-morbid conditions.</p>", "links"=>[], "tags"=>["co-morbid"], "article_id"=>371280, "categories"=>["Mental Health"], "users"=>["Berit Kerner", "Christophe G. Lambert", "Bengt O. Muthén"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0028477.t004", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Co_occurrence_of_co_morbid_conditions_/371280", "title"=>"Co-occurrence of co-morbid conditions.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-12-21 00:21:20"}
• {"files"=>["https://ndownloader.figshare.com/files/700796"], "description"=>"#<p>Age was missing in 8 individuals, 5 males and 3 females, all of whom clustered into Latent Class 3.</p><p>*Significant at the 0.05 level in the Wald Chi-Square test when testing the equality of means across the latent classes.</p><p>SUBA, substance abuse; OCD, obsessive compulsive disorder; PD, panic disorder; SP, social and specific phobia; ED, eating disorder; ADHD, attention-deficit hyperactivity disorder; ALCAB, alcohol abuse; ALCDEP, alcohol dependence; NIC, nicotine dependence; PSYCH, psychotic symptoms (presence of hallucinations and/or delusions).</p>", "links"=>[], "tags"=>["bipolar"], "article_id"=>371179, "categories"=>["Mental Health"], "users"=>["Berit Kerner", "Christophe G. Lambert", "Bengt O. Muthén"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0028477.t001", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Demographic_description_of_the_bipolar_disorder_sample_and_controls_/371179", "title"=>"Demographic description of the bipolar disorder sample and controls.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-12-21 00:19:39"}
• {"files"=>["https://ndownloader.figshare.com/files/700395"], "description"=>"<p>Co-morbid conditions might indicate heterogeneity in BPD. Latent class mixture modeling is a multivariate statistical approach to heterogeneity in data. The figure shows the co-morbidity profile of the three latent classes of BPD patients. Latent Class 1 (red line and ○ symbol) consisted of BPD patients with substance abuse and/or psychosis and a low probability of endorsing alcohol dependence. Class 2 (green line and Δ symbol) was BPD patients with a high probability of endorsing substance abuse and alcohol dependence. The probability of endorsing nicotine dependence in this class was the highest of all latent classes. Regarding obsessive compulsive disorder, panic disorder, social phobia, eating disorder, and attention-deficit hyperactivity disorder, Class 1 and Class 2 were not clearly differentiated. Individuals in Class 3 (blue line and □ symbol) were diagnosed with BPD, but their probability of endorsing any co-morbid condition was very low. The x-axis indicates the co-morbid conditions included in the LCA. The y-axis represents the probability of endorsing co-morbid conditions scaled from 0% to 100%. SUBA, substance abuse; OCD, obsessive compulsive disorder; PD, panic disorder; SP, social and specific phobia; ED, eating disorder; ADHD, attention-deficit hyperactivity disorder; ALCAB, alcohol abuse; ALCDEP, alcohol dependence; NIC, nicotine dependence; PSYCH, psychotic symptoms (presence of hallucinations and/or delusions).</p>", "links"=>[], "tags"=>["co-morbid", "conditions", "bipolar"], "article_id"=>370780, "categories"=>["Mental Health"], "users"=>["Berit Kerner", "Christophe G. Lambert", "Bengt O. Muthén"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0028477.g002", "stats"=>{"downloads"=>1, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Latent_class_solution_of_co_morbid_conditions_in_bipolar_disorder_BPD_/370780", "title"=>"Latent class solution of co-morbid conditions in bipolar disorder (BPD).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-12-21 00:13:00"}
• {"files"=>["https://ndownloader.figshare.com/files/700967"], "description"=>"<p>This table shows the minor allele frequencies for each SNP, as well as the dependent average latent class membership probability for each genotype. SNP, single nucleotide polymorphism; MAF, minor allele frequency; DD, homozygotes for the minor allele; Dd, heterozygotes for the minor allele; dd, homozygotes for the major allele.</p>", "links"=>[], "tags"=>["counts", "snps", "genome-wide"], "article_id"=>371346, "categories"=>["Mental Health"], "users"=>["Berit Kerner", "Christophe G. Lambert", "Bengt O. Muthén"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0028477.t006", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Genotype_counts_for_SNPs_with_genome_wide_significant_associations_/371346", "title"=>"Genotype counts for SNPs with genome-wide significant associations.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-12-21 00:22:26"}

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• {"unique-ip"=>"5", "full-text"=>"5", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"9"}
• {"unique-ip"=>"8", "full-text"=>"18", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"10"}
• {"unique-ip"=>"14", "full-text"=>"14", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"1", "cited-by"=>"1", "year"=>"2020", "month"=>"11"}
• {"unique-ip"=>"5", "full-text"=>"20", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"1", "cited-by"=>"1", "year"=>"2020", "month"=>"12"}
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Relative Metric

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F1000Prime