Obsessive-compulsive disorder (OCD) is a common, debilitating neuropsychiatric illness with complex genetic etiology. The International OCD Foundation Genetics Collaborative (IOCDF-GC) is a multi-national collaboration established to discover the genetic variation predisposing to OCD. A set of individuals affected with DSM-IV OCD, a subset of their parents, and unselected controls, were genotyped with several different Illumina SNP microarrays. After extensive data cleaning, 1,465 cases, 5,557 ancestry-matched controls and 400 complete trios remained, with a common set of 469,410 autosomal and 9,657 X-chromosome SNPs. Ancestry-stratified case-control association analyses were conducted for three genetically-defined subpopulations and combined in two meta-analyses, with and without the trio-based analysis. In the case-control analysis, the lowest two p-values were located within DLGAP1 (p=2.49×10-6 and p=3.44×10-6), a member of the neuronal postsynaptic density complex. In the trio analysis, rs6131295, near BTBD3, exceeded the genome-wide significance threshold with a p-value=3.84 × 10-8. However, when trios were meta-analyzed with the combined case-control samples, the p-value for this variant was 3.62×10-5, losing genome-wide significance. Although no SNPs were identified to be associated with OCD at a genome-wide significant level in the combined trio-case-control sample, a significant enrichment of methylation-QTLs (p<0.001) and frontal lobe eQTLs (p=0.001) was observed within the top-ranked SNPs (p<0.01) from the trio-case-control analysis, suggesting these top signals may have a broad role in gene expression in the brain, and possibly in the etiology of OCD.
Genetic association studies of SLC6A4 (SERT) and obsessive-compulsive disorder (OCD) have been equivocal. We genotyped 1241 individuals in 278 pedigrees from the OCD Collaborative Genetics Study for 13 single-nucleotide polymorphisms, for the linked polymorphic region (LPR) indel with molecular haplotypes at rs25531, for VNTR polymorphisms in introns 2 and 7 and for a 381-bp deletion 3 0 to the LPR. We analyzed using the FamilyBased Association Test (FBAT) under additive, dominant, recessive and genotypic models, using both OCD and sex-stratified OCD as phenotypes. Two-point FBAT analysis detected association between Int2 (P = 0.0089) and Int7 (P = 0.0187) (genotypic model). Sex-stratified two-point analysis showed strong association in females with Int2 (P < 0.0002), significant after correction for linkage disequilibrium, and multiple marker and model testing (P Adj = 0.0069). The SLC6A4 gene is composed of two haplotype blocks (our data and the HapMap); FBAT whole-marker analysis conducted using this structure was not significant. Several noteworthy nonsignificant results have emerged. Unlike Hu et al., we found no evidence for overtransmission of the LPR L A allele (genotype relative risk = 1.11, 95% confidence interval: 0.77-1.60); however, rare individual haplotypes containing L A with P < 0.05 were observed. Similarly, three individuals (two with OCD/OCPD) carried the rare I425V SLC6A4 variant, but none of them passed it on to their six OCD-affected offspring, suggesting that it is unlikely to be solely responsible for the 'OCD plus syndrome', as reported by Ozaki et al. In conclusion, we found evidence of genetic association at the SLC6A4 locus with OCD. A noteworthy lack of association at the LPR, LPR-rs25531 and rare 425V variants suggests that hypotheses about OCD risk need revision to accommodate these new findings, including a possible gender effect.
Background: Non-suicidal self-injury (NSSI) may be understood as a physical and behavioral expression of emotional distress. Over the past 70 years, it has been variably formulated as a type of emotional reaction to various stressors. NSSI has complex goals, sometimes implicit, but overall it serves as a transient psychological relief. Many believe that NSSI is a maladaptive behavior and is not related to suicide, with the primary differentiating factor between suicide and NSSI being the ‘intention’ to die. NSSI is an important mental health problem in current modern societies, and it is part of a trend in current psychiatric and mental health practice to medicalize maladaptive behaviors or psychological distress. Aims: To review the prevalence, associated factors, purpose, and psychological and social significance of NSSI in developing countries. Method: This article is a narrative review. However, of the total 1,094 articles, 13 articles were included to derive information on the prevalence and methods of NSSI in the developing country. Results: NSSI rates are very variable, ranging from 11.5% to as high as 33.8%, depending on the nature of the sample and study design, but data show an increasing trend globally, including in developing countries. Conclusion: The recent emerging data does not support the notion that it is common in developed Western countries, though the meaning, context and reason for NSSI might differ in developing and developed countries. NSSI is almost equally prevalent in both developing and developed countries.
Male infertility, affecting as many as 10%o of the adult population, is an extremely prevalent disorder. In most cases, the cause of the condition is unknown, and genetic factors that might affect male fertility, other than some sequences on the Y chromosome, have not been identified. We report here that male mice heterozygous for a targeted mutation of the apolipoprotein B (apo B) gene exhibit severely compromised fertility. Sperm from these mice failed to fertilize eggs both in vivo and in vitro. However, these sperm were able to fertilize eggs once the zona pellucida was removed but displayed persistent abnormal binding to the egg after fertilization. In vitro fertilization-related and other experiments revealed reduced sperm motility, survival time, and sperm count also contributed to the infertility phenotype. Recognition of the infertility phenotype led to the identification of apo B mRNA in the testes and epididymides of normal mice, and these transcripts were substantially reduced in the affected animals. Moreover, when the genomic sequence encoding human apo B was introduced into these animals, normal fertility was restored. These findings suggest that this genetic locus may have an important impact on male fertility and identify a previously unrecognized function for apo B.Apolipoprotein B (apo B) is one of several apolipoproteins that play key roles in lipoprotein metabolism (1). Plasma levels of apo B are an important risk factor for coronary heart disease, and apo B is the ligand for receptor-mediated removal of low density lipoprotein particles from circulation (1, 2). Mutations in apo B result in familial hypobetalipoproteinemia in humans (1, 3). These data and studies of mutations in the other apolipoprotein genes have established a central role for these molecules in determining the risk of cardiovascular disease.Recent studies, however, have suggested involvement of one or more apolipoproteins in other organ systems as well. For example, a variant of apolipoprotein E, apolipoprotein E4, correlates strongly with development of Alzheimer disease (4). While the mechanism by which inheritance of this genetic variant predisposes to Alzheimer disease is unknown, the findings provide impetus for examining possible roles of the apolipoproteins outside the cardiovascular system, with the ultimate goal of better understanding, predicting, and treating a wider variety of human diseases.In an effort to produce animal models of apo B deficiency, we and others have inactivated the mouse gene that encodes this protein by use of targeted mutagenesis in embryonic stem cells (5, 6). Homozygotes for null apo B alleles developed neural tube defects and died in utero (5, 6), while homozygotes for a truncated apo B allele showed incomplete penetrance for embryonic lethality (7). Heterozygotes for the null allele showed reduced cholesterol levels (5, 6) and we also noticed infertility in a majority of the male heterozygotes that were derived from female heterozyzgotes of the Fl generation (5). These latter fi...
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