Jurg Ott

Interaction Between the Serotonin Transporter Gene (5-HTTLPR), Stressful Life Events, and Risk of Depression: A Meta-analysis

CONTEXT Substantial resources are being devoted to identify candidate genes for complex mental and behavioral disorders through inclusion of environmental exposures following the report of an interaction between the serotonin transporter linked polymorphic region (5-HTTLPR) and stressful life events on an increased risk of major depression. OBJECTIVE To conduct a meta-analysis of the interaction between the serotonin transporter gene and stressful life events on depression using both published data and individual-level original data. DATA SOURCES Search of PubMed, EMBASE, and PsycINFO databases through March 2009 yielded 26 studies of which 14 met criteria for the meta-analysis. STUDY SELECTION Criteria for studies for the meta-analyses included published data on the association between 5-HTTLPR genotype (SS, SL, or LL), number of stressful life events (0, 1, 2, > or = 3) or equivalent, and a categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or the International Statistical Classification of Diseases, 10th Revision (ICD-10) or use of a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies published prior to 2008 that met inclusion criteria. Of the 14 studies included in the meta-analysis, 10 were also included in a second sex-specific meta-analysis of original individual-level data. DATA EXTRACTION Logistic regression was used to estimate the effects of the number of short alleles at 5-HTTLPR, the number of stressful life events, and their interaction on depression. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated separately for each study and then weighted averages of the individual estimates were obtained using random-effects meta-analysis. Both sex-combined and sex-specific meta-analyses were conducted. Of a total of 14,250 participants, 1769 were classified as having depression; 12,481 as not having depression. RESULTS In the meta-analysis of published data, the number of stressful life events was significantly associated with depression (OR, 1.41; 95% CI,1.25-1.57). No association was found between 5-HTTLPR genotype and depression in any of the individual studies nor in the weighted average (OR, 1.05; 95% CI, 0.98-1.13) and no interaction effect between genotype and stressful life events on depression was observed (OR, 1.01; 95% CI, 0.94-1.10). Comparable results were found in the sex-specific meta-analysis of individual-level data. CONCLUSION This meta-analysis yielded no evidence that the serotonin transporter genotype alone or in interaction with stressful life events is associated with an elevated risk of depression in men alone, women alone, or in both sexes combined.

A haplotype-based 'haplotype relative risk' approach to detecting allelic associations

A novel variation of the Haplotype Relative Risk (HRR) of Rubinstein et al. [Hum Immunol 1981;3:384] is proposed, in order to glean increased information about linkage disequilibrium or allelic associations by analyzing haplotype-based data rather than genotypic data. It is shown that statistical tests based on our design give much higher power than those based on the original HRR approach. Several additional nonparametric tests based on the same data are analyzed, and power is computed for each of them. Further, parametric likelihood methods are applied to testing linkage equilibrium, and estimating delta, the coefficient of linkage disequilibrium, from the same data.

Strong association of the Y402H variant in complement factor H at 1q32 with susceptibility to age-related macular degeneration

Using a large sample of cases and controls from a single center, we show that a T-->C substitution in exon 9 (Y402H) of the complement factor H gene is strongly associated with susceptibility to age-related macular degeneration, the most common cause of blindness in the elderly. Frequency of the C allele was 0.61 in cases, versus 0.34 in age-matched controls (P<1x10(-24)). Genotype frequencies also differ markedly between cases and controls (chi2=112.68 [2 degrees of freedom]; P<1x10(-24)). A multiplicative model fits the data well, and we estimate the population frequency of the high-risk C allele to be 0.39 (95% confidence interval 0.36-0.42) and the genotype relative risk to be 2.44 (95% confidence interval 2.08-2.83) for TC heterozygotes and 5.93 (95% confidence interval 4.33-8.02) for CC homozygotes.

The BRCA1-interacting helicase BRIP1 is deficient in Fanconi anemia

Seven Fanconi anemia–associated proteins (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG and FANCL) form a nuclear Fanconi anemia core complex that activates the monoubiquitination of FANCD2, targeting FANCD2 to BRCA1-containing nuclear foci. Cells from individuals with Fanconi anemia of complementation groups D1 and J (FA-D1 and FA-J) have normal FANCD2 ubiquitination. Using genetic mapping, mutation identification and western-blot data, we identify the defective protein in FA-J cells as BRIP1 (also called BACH1), a DNA helicase that is a binding partner of the breast cancer tumor suppressor BRCA1.

Mathematical multi-locus approaches to localizing complex human trait genes

Statistical analysis methods for gene mapping originated in counting recombinant and non-recombinant offspring, but have now progressed to sophisticated approaches for the mapping of complex trait genes. Here, we outline new statistical methods that capture the simultaneous effects of multiple gene loci and thereby achieve a more global view of gene action and interaction than is possible by traditional gene-by-gene analysis. We aim to show that the work of statisticians goes far beyond the running of computer programs.

Power and sample size calculations for case-control genetic association tests when errors are present: application to single nucleotide polymorphisms.

The purpose of this work is to quantify the effects that errors in genotyping have on power and the sample size necessary to maintain constant asymptotic Type I and Type II error rates (SSN) for case-control genetic association studies between a disease phenotype and a di-allelic marker locus, for example a single nucleotide polymorphism (SNP) locus. We consider the effects of three published models of genotyping errors on the chi-square test for independence in the 2 × 3 table. After specifying genotype frequencies for the marker locus conditional on disease status and error model in both a genetic model-based and a genetic model-free framework, we compute the asymptotic power to detect association through specification of the test’s non-centrality parameter. This parameter determines the functional dependence of SSN on the genotyping error rates. Additionally, we study the dependence of SSN on linkage disequilibrium (LD), marker allele frequencies, and genotyping error rates for a dominant disease model. Increased genotyping error rate requires a larger SSN. Every 1% increase in sum of genotyping error rates requires that both case and control SSN be increased by 2–8%, with the extent of increase dependent upon the error model. For the dominant disease model, SSN is a nonlinear function of LD and genotyping error rate, with greater SSN for lower LD and higher genotyping error rate. The combination of lower LD and higher genotyping error rates requires a larger SSN than the sum of the SSN for the lower LD and for the higher genotyping error rate.

Desmoglein 4 in Hair Follicle Differentiation and Epidermal Adhesion: Evidence from Inherited Hypotrichosis and Acquired Pemphigus Vulgaris

Cell adhesion and communication are interdependent aspects of cell behavior that are critical for morphogenesis and tissue architecture. In the skin, epidermal adhesion is mediated in part by specialized cell-cell junctions known as desmosomes, which are characterized by the presence of desmosomal cadherins, known as desmogleins and desmocollins. We identified a cadherin family member, desmoglein 4, which is expressed in the suprabasal epidermis and hair follicle. The essential role of desmoglein 4 in skin was established by identifying mutations in families with inherited hypotrichosis, as well as in the lanceolate hair mouse. We also show that DSG4 is an autoantigen in pemphigus vulgaris. Characterization of the phenotype of naturally occurring mutant mice revealed disruption of desmosomal adhesion and perturbations in keratinocyte behavior. We provide evidence that desmoglein 4 is a key mediator of keratinocyte cell adhesion in the hair follicle, where it coordinates the transition from proliferation to differentiation.

A putative RUNX1 binding site variant between SLC9A3R1 and NAT9 is associated with susceptibility to psoriasis

Psoriasis (OMIM 177900) is a chronic inflammatory skin disorder of unknown pathogenesis affecting ∼2% of the Western population. It occurs more frequently in individuals with human immunodeficiency virus, and 20–30% of individuals with psoriasis have psoriatic arthritis. Psoriasis is associated with HLA class I alleles, and previous linkage analysis by our group identified a second psoriasis locus at 17q24–q25 (PSORS2; ref. 7). Linkage to this locus was confirmed with independent family sets. Additional loci have also been proposed to be associated with psoriasis. Here we describe two peaks of strong association with psoriasis on chromosome 17q25 separated by 6 Mb. Associated single-nucleotide polymorphisms (SNPs) in the proximal peak lie in or near SLC9A3R1 (also called EBP50 and NHERF1) and NAT9, a new member of the N-acetyltransferase family. SLC9A3R1 is a PDZ domain–containing phosphoprotein that associates with members of the ezrin-radixin-moesin family and is implicated in diverse aspects of epithelial membrane biology and immune synapse formation in T cells. The distal peak of association is in RAPTOR (p150 target of rapamycin (TOR)-scaffold protein containing WD-repeats). Expression of SLC9A3R1 is highest in the uppermost stratum Malpighi of psoriatic and normal skin and in inactive versus active T cells. A disease-associated SNP lying between SLC9A3R1 and NAT9 leads to loss of RUNX1 binding. This is the second example of loss of a RUNX1 binding site associated with susceptibility to an autoimmune disease. It also suggests defective regulation of SLC9A3R1 or NAT9 by RUNX1 as a susceptibility factor for psoriasis.

The p53MH algorithm and its application in detecting p53-responsive genes

A computer algorithm, p53MH, was developed, which identifies putative p53 transcription factor DNA-binding sites on a genomewide scale with high power and versatility. With the sequences from the human and mouse genomes, putative p53 DNA-binding elements were identified in a scan of 2,583 human genes and 1,713 mouse orthologs based on the experimental data of el-Deiry et al. [el-Deiry, W. S., Kern, S. E., Pietenpol, J. A., Kinzler, K. W. & Vogelstein, B. (1992) Nat. Genet. 1, 45–49] and Funk et al. [Funk, W. D., Pak, D. T., Karas, R. H., Wright, W. E. & Shay, J. W. (1992) Mol. Cell. Biol. 12, 2866–2871] (http://linkage.rockefeller.edu/p53). The p53 DNA-binding motif consists of a 10-bp palindrome and most commonly a second related palindrome linked by a spacer region. By scanning from the 5′ to 3′ end of each gene with an additional 10-kb nucleotide sequence appended at each end (most regulatory DNA elements characterized in the literature are in these regions), p53MH computes the binding likelihood for each site under a discrete discriminant model and then outputs ordered scores, corresponding site positions, sequences, and related information. About 300 genes receiving scores greater than a theoretical cut-off value were identified as potential p53 targets. Semiquantitative reverse transcription–PCR experiments were performed in 2 cell lines on 16 genes that were previously unknown regarding their functional relationship to p53 and were found to have high scores in either proximal promoter or possible distal enhancer regions. Ten (∼63%) of these genes responded to the presence of p53.

Family-based association studies support a sexually dimorphic effect of COMT and MAOA on genetic susceptibility to obsessive-compulsive disorder.

BACKGROUND Obsessive-compulsive disorder (OCD) is a common and severe psychiatric illness that affects 1-3% of the population and presents a well-established co-morbidity with major depressive disorder (MDD). Twin and family studies have suggested a genetic component in the etiology of OCD, although the mode of inheritance is unknown. Pharmacotherapy of the disease implicates both serotonergic and dopaminergic pathways. Previously, guided by the 22q11 microdeletion-related psychiatric phenotype, we provided evidence for a sexually dimorphic association between OCD and the gene for catechol-O-methyltransferase (COMT). In this report, we use 110 nuclear OCD families to analyze the inheritance of variants of COMT and monoamine oxidase-A (MAOA), another gene modulating monoamine metabolism. METHODS A sample of 110 nuclear OCD families was collected, and lifetime diagnoses were ascertained using the Diagnostic Interview for Genetic Studies (DIGS). DNA was genotyped for functional variants of the COMT and MAO genes, and allele inheritance was examined using the Transmission Disequilibrium Test (TDT) and Haplotype-based Haplotype Relative Risk (HHRR) test. RESULTS We provide evidence supporting the previously reported sexually dimorphic association between low COMT enzymatic activity and OCD. We also provide evidence for a similar sexually dimorphic association between OCD and an allele of the MAOA gene, previously linked to high MAO-A enzymatic activity. In agreement with the well-established action of MAO-A inhibitors as antidepressants, this association is particularly marked among male OCD probands with co-morbid MDD, who represent more than 50% of our male OCD sample. CONCLUSIONS Our analysis indicates that variants of two genes modulating monoamine metabolism contribute significantly to OCD susceptibility. Most importantly, an unexpected sexually dimorphic pattern of genetic susceptibility to OCD is revealed and suggests the possibility that profound gender differences in genetic predisposition may exist not only for other OCD susceptibility genes, but for an array of other psychiatric disorders as well.