Genetic analysis of neuropsychiatric disorders in a South American population isolate.

Bipolar disorder (BP) and schizophrenia are severe neuropsychiatric conditions that are among the leading causes of morbidity and chronic disability world-wide. Both conditions are characterised by a substantial genetic heterogeneity, which has complicated the search for susceptibility loci. One strategy to tackle this difficulty lies in the study of population isolates that are characterised by a reduced genetic heterogeneity. In this thesis, I have therefore conducted genetic studies of BP and schizophrenia in the well-characterised South American population isolate of Antioquia, Colombia. Our group has recently reported the results of a linkage scan of six Antioquian families segregating severe BP. Here, I performed a follow-up study of a candidate region on chromosome 5q33. I sequenced the CLINT 1 gene, a functional candidate that has also been implicated in schizophrenia, in affecteds from four BP pedigrees from the original linkage study and identified three single base pair variants, all of which had been previously described. A transmission distortion test of one of these variants, rs 11955293, in a sample of 176 unrelated BP patients from Antioquia and their parents found no evidence of association with BP. Although these results do not rule out a minor effect of the CLINT1 gene on susceptibility to the disorder in Antioquia, other loci are likely to be of greater significance. This includes other genes on chromosome 5q33, but also other candidate regions in the genome. To further explore the latter possibility, I conducted a whole-genome linkage scan in an additional nine pedigrees with severe BP from Antioquia and analysed the obtained genotype data jointly with that of the initial linkage scan. Using parametric and non-parametric linkage approaches, I explored three different diagnostic models: a narrow model including only BP type I (BPI) as affected a model including BPI and II and major unipolar depression and a third model including only individuals who had experienced psychosis as affected. This second linkage scan found evidence for a number of candidate regions, including chromosome 13q33 for BPI, chromosomes lpl3-31 and lq25-31 for mood disorders, chromosome 12ct-ql4 for mood disorders, and chromosomes 2q24-31 and 16pl2 for psychosis. Encouragingly, many of these loci had previously been pinpointed as BP susceptibility loci in other populations on the other hand, we also identified a novel locus on chromosome 12q. While the use of population isolates can help decrease the genetic heterogeneity of a complex disease, complementary strategies can be used to reduce this heterogeneity even further. In studying the NOS1AP gene, a functional candidate on chromosome lq23 that is involved in glutamatergic neurotransmission, in a sample of 102 unrelated Antioquian schizophrenia patients and their parents, I have therefore used both categorical and dimensional approaches to the disease phenotype. In the categorical approach, I conducted an analysis for association between the NOS1AP gene and DSM-IV schizophrenia by TDT. For the dimensional approach, two clinical scales measuring positive and negative symptoms, SANS and SAPS, were applied to all patients and dimensional scores were obtained from these scales by factors analysis. I then performed quantitative TDT analysis of the dimensional scores. My analyses found association to both DSM-IV schizophrenia and a clinical dimension capturing negative symptoms, in line with a role of NOS1AP in glutamatergic neurotransmission. The results of these analyses also underline the usefulness of a dimensional approach in psychiatric genetics

Genome-Wide Linkage Scan of Bipolar Disorder in a Colombian Population Isolate Replicates Loci on Chromosomes 7p21–22, 1p31, 16p12 and 21q21–22 and Identifies a Novel Locus on Chromosome 12q

Background/Aims: Bipolar disorder (BP) is a severe psychiatric illness, characterised by alternating episodes of depression and mania, which ranks among the top ten causes of morbidity and life-long disability world-wide. We have previously performed a whole-genome linkage scan on 6 pedigrees segregating severe BP from the well-characterised population isolate of Antioquia, Colombia. We recently collected genotypes for the same set of 382 autosomal microsatellite markers in 9 additional Antioquian BP pedigrees. Here, we report the analysis of the combined pedigree set

Contribution of common and rare variants to bipolar disorder susceptibility in extended pedigrees from population isolates.

Current evidence from case/control studies indicates that genetic risk for psychiatric disorders derives primarily from numerous common variants, each with a small phenotypic impact. The literature describing apparent segregation of bipolar disorder (BP) in numerous multigenerational pedigrees suggests that, in such families, large-effect inherited variants might play a greater role. To identify roles of rare and common variants on BP, we conducted genetic analyses in 26 Colombia and Costa Rica pedigrees ascertained for bipolar disorder 1 (BP1), the most severe and heritable form of BP. In these pedigrees, we performed microarray SNP genotyping of 838 individuals and high-coverage whole-genome sequencing of 449 individuals. We compared polygenic risk scores (PRS), estimated using the latest BP1 genome-wide association study (GWAS) summary statistics, between BP1 individuals and related controls. We also evaluated whether BP1 individuals had a higher burden of rare deleterious single-nucleotide variants (SNVs) and rare copy number variants (CNVs) in a set of genes related to BP1. We found that compared with unaffected relatives, BP1 individuals had higher PRS estimated from BP1 GWAS statistics (P = 0.001 ~ 0.007) and displayed modest increase in burdens of rare deleterious SNVs (P = 0.047) and rare CNVs (P = 0.002 ~ 0.033) in genes related to BP1. We did not observe rare variants segregating in the pedigrees. These results suggest that small-to-moderate effect rare and common variants are more likely to contribute to BP1 risk in these extended pedigrees than a few large-effect rare variants

Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD

TrpA1 Regulates Thermal Nociception in Drosophila

Pain is a significant medical concern and represents a major unmet clinical need. The ability to perceive and react to tissue-damaging stimuli is essential in order to maintain bodily integrity in the face of environmental danger. To prevent damage the systems that detect noxious stimuli are therefore under strict evolutionary pressure. We developed a high-throughput behavioral method to identify genes contributing to thermal nociception in the fruit fly and have reported a large-scale screen that identified the Ca2+ channel straightjacket (stj) as a conserved regulator of thermal nociception. Here we present the minimal anatomical and neuronal requirements for Drosophila to avoid noxious heat in our novel behavioral paradigm. Bioinformatics analysis of our whole genome data set revealed 23 genes implicated in Ca2+ signaling that are required for noxious heat avoidance. One of these genes, the conserved thermoreceptor TrpA1, was confirmed as a bona fide “pain” gene in both adult and larval fly nociception paradigms. The nociceptive function of TrpA1 required expression within the Drosophila nervous system, specifically within nociceptive multi-dendritic (MD) sensory neurons. Therefore, our analysis identifies the channel TRPA1 as a conserved regulator of nociception

Effect Sizes in Experimental Pain Produced by Gender, Genetic Variants and Sensitization Procedures

Background: Various effects on pain have been reported with respect to their statistical significance, but a standardized measure of effect size has been rarely added. Such a measure would ease comparison of the magnitude of the effects across studies, for example the effect of gender on heat pain with the effect of a genetic variant on pressure pain. Methodology/Principal Findings: Effect sizes on pain thresholds to stimuli consisting of heat, cold, blunt pressure, punctuate pressure and electrical current, administered to 125 subjects, were analyzed for 29 common variants in eight human genes reportedly modulating pain, gender and sensitization procedures using capsaicin or menthol. The genotype explained 0–5.9% of the total interindividual variance in pain thresholds to various stimuli and produced mainly small effects (Cohen's d 0–1.8). The largest effect had the TRPA1 rs13255063T/rs11988795G haplotype explaining >5% of the variance in electrical pain thresholds and conferring lower pain sensitivity to homozygous carriers. Gender produced larger effect sizes than most variant alleles (1–14.8% explained variance, Cohen's d 0.2–0.8), with higher pain sensitivity in women than in men. Sensitization by capsaicin or menthol explained up to 63% of the total variance (4.7–62.8%) and produced largest effects according to Cohen's d (0.4–2.6), especially heat sensitization by capsaicin (Cohen's d = 2.6). Conclusions: Sensitization, gender and genetic variants produce effects on pain in the mentioned order of effect sizes. The present report may provide a basis for comparative discussions of factors influencing pain