![]() However, genetic heterogeneity can reduce the power to detect susceptibility variants when samples of BPD I and BPD II are combined for analysis. 17, 18, 19 One motivation for grouping the subtypes is that it remains possible that BPD II is a milder form of BPD I as opposed to being a distinct disorder. Several recent genome-wide genetic association studies and meta-analyses 2, 10 have jointly analyzed BPD I and BPD II subjects, 10, 11, 12, 13, 14, 15, 16 or have focused only on BPD I subjects. 9 The identification of BPD I and BPD II susceptibility genes may lead to more effective targets for therapy. Although BPD I and BPD II have been shown to co-segregate within families, 2, 8 the diverse clinical symptoms indicate that subtypes of the BPD phenotype exist and/or that phenotypic modifiers are involved. 2, 3 Recurrence of manic/depressive episodes and associated disabilities is common 5, 6, 7 and there exists no curative treatment. 1 The clinical course of BPD I and BPD II differ in that BPD I patients exhibit one or more manic episodes while BPD II patients are characterized by recurrent depressive episodes. The lifetime risks in the US population is 1% for BPD I and 1.1% for BPD II. The two most common subtypes of BPD are bipolar disorder I (BPD I) and bipolar disorder II (BPD II). 1, 2, 3, 4 With an overall heritability estimated at 80–90%, 2 these and other findings make clear that susceptibility to BPD has a very strong genetic basis that overlaps with the genetic susceptibility for other neuropsychiatric disorders. 2 Relatives of BPD probands are also at an increased risk of other related psychiatric disorders, such as psychotic, anxiety, substance abuse and impulse control disorders. 1 The risk of BPD for a first-degree relative of an affected individual is 9%, and the concordance rate for monozygotic twins is 40–45%. This report is among the first to use multiple rare variant analysis methods following common tagSNPs associations with BPD.īipolar disorder (BPD) affects ∼2.5% of the United States population aged 18 and older based on data from the population-based National Comorbidity Survey Replication. In addition, SNP × SNP interaction studies suggested that variants in several cAMP signaling pathway genes interact to increase the risk of BPD. ![]() After using newly developed methods to account for potential bias from sequencing BPD cases only, the results remained significant. We obtained a significant association for these variants in the combined sample using multiple methods for rare variant analysis. These single-nucleotide variants were genotyped in 999 BPD cases and 801 controls. We followed-up PDE10A’s association with BPD I by sequencing a 23-kb region in 30 subjects homozygous for seven minor allele risk SNPs and discovered eight additional rare variants (minor allele frequency <1%). ![]() Haplotype analysis supported the conclusion that variation in these genes is associated with BPD. Several statistically significant single-SNP associations were observed between BPD I and variants in the PDE10A gene and between BPD II and variants in the DISC1 and GNAS genes. Single SNP (single-nucleotide polymorphism), haplotype and SNP × SNP interactions were examined for association with BPD. A total of 1172 individuals with BPD I, 516 individuals with BPD II and 1728 controls were analyzed. As it is well established that cyclic adenosine monophosphate (cAMP) signaling regulates behavior, we tested variants in 29 genes that encode components of this signaling pathway for associations with BPD type I (BPD I) and BPD type II (BPD II). The genetic basis for bipolar disorder (BPD) is complex with the involvement of multiple genes. ![]()
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