Context Although genetic influences on bipolar disorder are well established, localization of genes that predispose to the illness has proven difficult. Given that genes predisposing to bipolar disorder may be transmitted without expression of the categorical clinical phenotype, one strategy for identifying risk genes is the use of quantitative endophenotypes. Objective The goal of the current study is to adjudicate neurocognitive endophenotypes for bipolar disorder. Design, Setting, and Participants 709 Latino individuals from the central valley of Costa Rica, Mexico City, Mexico, or San Antonio, Texas participated in the study. 660 of these persons were members of extended pedigrees with at least two siblings diagnosed with bipolar disorder (n=230). The remaining subjects were community controls drawn from each site and without personal or family history of bipolar disorder or schizophrenia. All subjects received psychodiagnostic interviews and comprehensive neurocognitive evaluations. Neurocognitive measures found to be heritable were entered into analyses designed to determine which tests are impaired in affected individuals, sensitive to genetic liability for the illness and genetically correlated with affection status. Main Outcome Measures The main outcome measure was neurocognitive test performance. Results Two of the 21 neurocognitive variables were not significantly heritable and were excluded from subsequent analyses. Patients with bipolar disorder were impaired on 6 of these cognitive measures compared to non-related healthy subjects. Non-bipolar first-degree relatives were impaired on five of these and three tests were genetically correlated with affection status: digit symbol coding, object delayed response, and immediate facial memory. Conclusions This large-scale extended pedigree study of cognitive functioning in bipolar disorder identified measures of processing speed, working memory and declarative (facial) memory as candidate endophenotypes for bipolar disorder.

As it is likely that both common and rare genetic variation are important for complex disease risk, studies that examine the full range of the allelic frequency distribution should be utilized to dissect the genetic influences on mental illness. The rate limiting factor for inferring an association between a variant and a phenotype is inevitably the total number of copies of the minor allele captured in the studied sample. For rare variation, with minor allele frequencies of 0.5% or less, very large samples of unrelated individuals are necessary to unambiguously associate a locus with an illness. Unfortunately, such large samples are often cost prohibitive. However, by using alternative analytic strategies and studying related individuals, particularly those from large multiplex families, it is possible to reduce the required sample size while maintaining statistical power. We contend that using whole genome sequence (WGS) in extended pedigrees provides a cost-effective strategy for psychiatric gene mapping that complements common variant approaches and WGS in unrelated individuals. This was our impetus for forming the "Pedigree-Based Whole Genome Sequencing of Affective and Psychotic Disorders" consortium. In this review, we provide a rationale for the use of WGS with pedigrees in modern psychiatric genetics research. We begin with a focused review of the current literature, followed by a short history of family-based research in psychiatry. Next, we describe several advantages of pedigrees for WGS research, including power estimates, methods for studying the environment, and endophenotypes. We conclude with a brief description of our consortium and its goals.

Objectives: Recent genome-wide association studies (GWASs) have identified numerous putative genetic polymorphisms associated with bipolar disorder (BD) and/or schizophrenia (SC). We hypothesized that a portion of these polymorphisms would also be associated with BD in the Latino American population. To identify such regions, we tested previously identified genetic variants associated with BD and/or SC and ancestral haploblocks containing these single nucleotide polymorphisms (SNPs) in a sample of Latino subjects with BD. Methods:A total of 2254 Latino individuals were genotyped for 91 SNPs identified in previous BD and/or SC GWASs, along with selected SNPs in strong linkage disequilibrium with these markers. Family-based single marker and haplotype association testing was performed using the PBAT software package. Empirical P-values were derived from 10 000 permutations.Results: Associations of eight a priori GWAS SNPs with BD were replicated with nominal (P≤.05) levels of significance. These included SNPs within nuclear factor I A (NFIA), serologically defined colon cancer antigen 8 (SDCCAG8), lysosomal associated membrane protein 3 (LAMP3), nuclear factor kappa B subunit 1 (NFKB1), major histocompatibility complex, class I, B (HLA-B) and 5′-nucleotidase, cytosolic II (NT5C2) and SNPs within intragenic regions microRNA 6828 (MIR6828)-solute carrier family 7 member 14 (SLC7A14) and sonic hedgehog (SHH)-long intergenic non-protein coding RNA 1006 (LINC01006). Of the 76 ancestral haploblocks that were tested for associations with BD, our top associated haploblock was located in LAMP3; however, the association did not meet statistical thresholds of significance following Bonferroni correction. Conclusions:These results indicate that some of the gene variants found to be associated with BD or SC in other populations are also associated with BD risk in Latinos.Variants in six genes and two intragenic regions were associated with BD in our Latino sample and provide additional evidence for overlap in genetic risk between SC and BD. K E Y W O R D Sbipolar disorder, Central American, family studies, genetics, lysosomal associated membrane protein 3 (LAMP3), Latinos, Mexican, Mexican-American, nuclear factor kappa B subunit 1 (NFKB1), serologically defined colon cancer antigen 8 (SDCCAG8)

Bipolar disorder and alcohol use disorder (AUD) have a high rate of comorbidity, more than 50% of individuals with bipolar disorder also receive a diagnosis of AUD in their lifetimes. Although both disorders are heritable, it is unclear if the same genetic factors mediate risk for bipolar disorder and AUD. We examined 733 Costa Rican individuals from 61 bipolar pedigrees. Based on a best-estimate process, 32% of the sample met criteria for bipolar disorder, 17% had a lifetime AUD diagnosis, 32% met criteria for lifetime nicotine dependence, and 21% had an anxiety disorder. AUD, nicotine dependence and anxiety disorders were relatively more common among individuals with bipolar disorder than in their non-bipolar relatives. All illnesses were shown to be heritable and bipolar disorder was genetically correlated with AUD, nicotine dependence and anxiety disorders. The genetic correlation between bipolar and AUD remained when controlling for anxiety, suggesting that unique genetic factors influence risk for comorbid bipolar and AUD independent of anxiety. Our findings provide evidence for shared genetic effects on bipolar disorder and AUD risk. Demonstrating that common genetic factors influence these independent diagnostic constructs could help to refine our diagnostic nosology.

Background Although genetic influences on bipolar I disorder are well established, localization of genes that predispose to the illness has been difficult. Some genes predisposing to bipolar I disorder may be transmitted without expression of the categorical clinical phenotype. One strategy to overcome this obstacle is the use of quantitative endophenotypes as has been done for other psychotic disorders. Methods We analyzed 30 bipolar I extended families (300 subjects, average family size 10.34 members, range: 2–31) and 20 unrelated healthy controls from a Costa Rican sample. Heritability and genetic correlation of the state and trait scale from the Anxiety State and Trait Inventory was computed by using the general linear model (Solar package software). We also assessed variation of both scores among groups (patients, relatives and controls) and tested independence of affection status. Results Heritability for state is 0.45 (SE=0.11, p=0.0000001) and for trait is 0.89 (SE=0.06, p=6.22e–29). Genetic correlation for state and trait is 0.29, (SE=0.12, p=0.038–3.19e-8). Bipolar I patients showed the highest trait score (F=12.17,[5,24], p=0.002), (bipolar I patients > relatives with other pathologies, > healthy relatives > unrelated healthy controls) with normal distribution in healthy individuals and no difference regarding depression and mania current status, (F=0.230, df=1, p=0.632) and (F=1.401, df=1, p=0.238) respectively, contrary to the state score. Limitations Confounding factors such as comorbid disorders could affect the interaction of subclinical anxiety with mania. Due to our limited budget we were not able to re-evaluate the subjects and conduct a test retest to assess the STAI reliability and mood state independence of anxiety traits over different times. Further research need to evaluate if anxiety traits are specially related to bipolar I disorder in comparison with other traits such as anger, attention or response inhibition deficit, pathological impulsivity or low self-directedness. Conclusions Anxiety state and trait are heritable and share some genetic factors but only trait showed normal distribution in healthy subjects, mood current status independence and significant liability for bipolar I disorder. A stair-step distribution of trait anxiety scores in the family members and controls based on their genetic proximity to affected individuals and diagnostic status suggests that trait anxiety could be an endophenotype in these bipolar I families.