Genome‐wide association analysis of age at onset in schizophrenia in a European‐American sample

We performed a genome‐wide association analysis to identify genetic variants influencing age at onset (AAO) and examine gene × gender interactions for AAO in schizophrenia (SCZ) using a European‐American sample (1,162 cases). Linear regression model in PLINK was used to test for associations with AAO while the GxE option was chosen to test for the influence of gene × gender interactions. The most significant association with AAO was observed with SNP rs7819815 (P = 3.10 × 10^?7) at 8q24.22. The next best signal was at 4q25 in COL25A1 gene (rs17039583, P = 4.30 × 10^?6) and the third region was at 4p16.1 (rs17407555, P = 4.56 × 10^?6, near RAF1P1, and rs4697924, P = 1.23 × 10^?5 within WDR1 gene). Conditional analysis on chromosome 4 indicated that 4p16.1 and 4q25 loci were independent. Furthermore, 2 SNPs (rs16834822 and rs16834824) at 1q43 in RYR2 showed strong associations in the female sample (P = 2.10 × 10^?6 and 2.33 × 10^?6, respectively) and strong gene × gender interactions in influencing AAO (P = 9.23 × 10^?7 and 1.15 × 10^?6, respectively) while the second best region showing gene × gender interaction was at 7q22.3 (rs179863, P = 2.33 × 10^?6). Using an independent sample of 1,068 cases, we could not replicate the associations for above top SNPs; however, we found nominal significance associations for their flanking SNPs (P < 0.05). These findings provide evidence of several genetic variants influencing AAO of SCZ. © 2011 Wiley‐Liss, Inc.     

Structural Genomic Variation as Risk Factor for Idiopathic Recurrent Miscarriage

Recurrent miscarriage (RM) is a multifactorial disorder with acknowledged genetic heritability that affects ～3% of couples aiming at childbirth. As copy number variants (CNVs) have been shown to contribute to reproductive disease susceptibility, we aimed to describe genome‐wide profile of CNVs and identify common rearrangements modulating risk to RM. Genome‐wide screening of Estonian RM patients and fertile controls identified excessive cumulative burden of CNVs (5.4 and 6.1 Mb per genome) in two RM cases possibly increasing their individual disease risk. Functional profiling of all rearranged genes within RM study group revealed significant enrichment of loci related to innate immunity and immunoregulatory pathways essential for immune tolerance at fetomaternal interface. As a major finding, we report a multicopy duplication (61.6 kb) at 5p13.3 conferring increased maternal risk to RM in Estonia and Denmark (meta‐analysis, n = 309/205, odds ratio = 4.82, P = 0.012). Comparison to Estonian population‐based cohort (total, n = 1000) confirmed the risk for Estonian female cases (P = 7.9 × 10^?4). Datasets of four cohorts from the Database of Genomic Variants (total, n = 5,846 subjects) exhibited similar low duplication prevalence worldwide (0.7%–1.2%) compared to RM cases of this study (6.6%–7.5%). The CNV disrupts PDZD2 and GOLPH3 genes predominantly expressed in placenta and it may represent a novel risk factor for pregnancy complications.     

Genome‐wide compound heterozygosity analysis highlighted 4 novel susceptibility loci for congenital heart disease in Chinese population

Genome‐wide association studies (GWASs) have achieved great success in deciphering the genetic cause of congenital heart disease (CHD). However, the heritability of CHD remains to be clarified, and numerous genetic factors responsible for occurrence of CHD are yet unclear. In this study, we performed a genome‐wide search for relaxed forms of compound heterozygosity (CH) in association with CHD using our existing GWAS data including 2265 individuals (957 CHD cases and 1308 controls). CollapsABEL was used to iteratively test the association between the CH genotype and the CHD phenotype in a sliding window manner. We highlighted 17 genetic loci showing suggestive CH‐like associations with CHD (P < 5 × 10^?8), among which 4 genetic loci had expression quantitative trait loci (eQTL) effects in blood (P_eQTL < 0.01). After conditional association analysis, each loci had only 1 independently effective signal reaching the significance threshold (rs2071477/rs3129299 at 6p21.32, P = 2.47 × 10^?10; rs10773097/rs2880921 at 12q24.31, P = 3.30 × 10^?8; rs73032040/rs7259476 at 19q13.11, P = 1.14 × 10^?8; rs10416386/rs4239517 at 19q13.31, P = 1.15 × 10^?9), together explained 7.83% of the CHD variance. Among these 4 associated loci, outstanding candidates for CHD‐associated genes included UBC, CFM2, ZNF302, LYPD3 and CADM4. Although replication studies with larger sample size are warranted, the first CH GWAS of CHD may extend our current knowledge of the genetic contributions to CHD in the Han Chinese population.     

Genome‐wide association study of lncRNA polymorphisms with bone mineral density

Recent studies suggested that long noncoding RNAs (lncRNAs) were widely transcribed in the genome, but their potential roles in the genetic complexity of human disorders required further exploration. The purpose of the present study was to explore genetic polymorphisms of lncRNAs associated with bone mineral density (BMD) and its potential value. Based on the lncRNASNP database, 55,906 lncSNPs were selected to conduct a genome‐wide association study meta‐analysis among 11,140 individuals of seven independent studies for BMDs at femoral neck (FN), lumbar spine, and total hip (HIP). Promising results were replicated in Genetic Factors for Osteoporosis Consortium (GEFOS Sequencing, n = 32,965). We found two lncRNA loci that were significantly associated with BMD. MEF2C antisense RNA 1 (MEF2C‐AS1) located at 5q14.3 was significantly associated with FN‐BMD after Bonferroni correction, and the strongest association signal was detected at rs6894139 (P = 3.03 × 10^?9). LOC100506136 rs6465531 located at 7q21.3 showed significant association with HIP‐BMD (P = 7.43 × 10^?7). MEF2C‐AS1 rs6894139 was replicated in GEFOS Sequencing with P‐value of 1.43 × 10^?23. Our results illustrated the important role of polymorphisms in lncRNAs in determining variations of BMD and provided justification and evidence for subsequent functional studies.     

Variants in 9p21 Predicts Severity of Coronary Artery Disease in a Chinese Han Population

Recent genome‐wide association studies identified the common genetic variants in 9p21 were associated with the coronary artery disease (CAD). However, whether this locus could predict the severity of CAD in Chinese Han population is unclear. 499 CAD patients who underwent coronary angiography (CAG) have been enrolled for this study. The single‐nucleotide polymorphisms rs2383207 and rs2383206 in 9p21 were genotyped in 499 CAG cases and 1519 controls in Chinese Han population. The gene dosage of 9p21 was stratified by the degree of vascular lesions and tested for association with the severity of CAD. Rs2383207 and rs2383206 demonstrated significant associations with 2‐vessel and 3‐vessel disease (P = 2.0×10^?3 and 1.9×10^?4, respectively). GG genotypes of rs2383206 occurred higher proportion of left main trunk (LM) disease (P = 6.0×10^?3). GG genotypes of rs2383207 occurred higher proportion of left anterior descending artery disease (LAD) and right CAD (RCA) (P = 2.7×10^?6 and 1.6×10^?4, respectively). The risk allele G of rs2383207 was associated with severity of CAD estimated by the Gensini score (P = 3.6×10^?5). Rs2383207 may strongly influence the development of CAD in Chinese Han population. The gene dosage in 9p21 could predict the severity of CAD.     

Genome‐wide association study of theta band event‐related oscillations identifies serotonin receptor gene HTR7 influencing risk of alcohol dependence

Event‐related brain oscillations (EROs) represent highly heritable neuroelectrical correlates of human perception and cognitive performance that exhibit marked deficits in patients with various psychiatric disorders. We report the results of the first genome‐wide association study (GWAS) of an ERO endophenotype—frontal theta ERO evoked by visual oddball targets during P300 response in 1,064 unrelated individuals drawn from a study of alcohol dependence. Forty‐two SNPs of the Illumina HumanHap 1 M microarray were selected from the theta ERO GWAS for replication in family‐based samples (N = 1,095), with four markers revealing nominally significant association. The most significant marker from the two‐stage study is rs4907240 located within ARID protein 5A gene (ARID5A) on chromosome 2q11 (unadjusted, Fisher's combined P = 3.68 × 10^?6). However, the most intriguing association to emerge is with rs7916403 in serotonin receptor gene HTR7 on chromosome 10q23 (combined P = 1.53 × 10^?4), implicating the serotonergic system in the neurophysiological underpinnings of theta EROs. Moreover, promising SNPs were tested for association with diagnoses of alcohol dependence (DSM‐IV), revealing a significant relationship with the HTR7 polymorphism among GWAS case–controls (P = 0.008). Significant recessive genetic effects were also detected for alcohol dependence in both case–control and family‐based samples (P = 0.031 and 0.042, respectively), with the HTR7 risk allele corresponding to theta ERO reductions among homozygotes. These results suggest a role of the serotonergic system in the biological basis of alcohol dependence and underscore the utility of analyzing brain oscillations as a powerful approach to understanding complex genetic psychiatric disorders. © 2010 Wiley‐Liss, Inc.     

A Genome‐Wide Search for Type 2 Diabetes Susceptibility Genes in an Extended Arab Family

Twenty percent of people aged 20 to 79 have type 2 diabetes (T2D) in the United Arab Emirates (UAE). Genome‐wide association studies (GWAS) to identify genes for T2D have not been reported for Arab countries. We performed a discovery GWAS in an extended UAE family (N = 178; 66 diabetic; 112 healthy) genotyped on the Illumina Human 660 Quad Beadchip, with independent replication of top hits in 116 cases and 199 controls. Power to achieve genome‐wide significance (commonly P = 5 × 10^?8) was therefore limited. Nevertheless, transmission disequilibrium testing in FBAT identified top hits at Chromosome 4p12‐p13 (KCTD8: rs4407541, P = 9.70 × 10^?6; GABRB1: rs10517178/rs1372491, P = 4.19 × 10^?6) and 14q13 (PRKD1: rs10144903, 3.92 × 10^?6), supported by analysis using a linear mixed model approximation in GenABEL (4p12‐p13 GABRG1/GABRA2: rs7662743, P_adj‐agesex = 2.06 × 10^?5; KCTD8: rs4407541, P_adj‐agesex = 1.42 × 10^?4; GABRB1: rs10517178/rs1372491, P_adj‐agesex = 0.027; 14q13 PRKD1: rs10144903, P_adj‐agesex = 6.95 × 10^?5). SNPs across GABRG1/GABRA2 did not replicate, whereas more proximal SNPs rs7679715 (P_adj‐agesex = 0.030) and rs2055942 (P_adj‐agesex = 0.022) at COX7B2/GABRA4 did, in addition to a trend distally at KCTD8 (rs4695718: P_adj‐agesex = 0.096). Modelling of discovery and replication data support independent signals at GABRA4 (rs2055942: P_{adj‐agesex‐combined} = 3 × 10^?4) and at KCTD8 (rs4695718: P_{adj‐agesex‐combined} = 2 × 10^?4). Replication was observed for PRKD1 rs1953722 (proxy for rs10144903; P_adj‐agesex = 0.031; P_{adj‐agesex‐combined} = 2 × 10^?4). These genes may provide important functional leads in understanding disease pathogenesis in this population.     

Genetic Factors in Nonsmokers with Age‐Related Macular Degeneration Revealed Through Genome‐Wide Gene‐Environment Interaction Analysis

Relatively little is known about the interaction between genes and environment in the complex etiology of age‐related macular degeneration (AMD). This study aimed to identify novel factors associated with AMD by analyzing gene‐smoking interactions in a genome‐wide association study of 1207 AMD cases and 686 controls of Caucasian background with genotype data on 668,238 single nucleotide polymorphisms (SNPs) after quality control. Participants’ history of smoking at least 100 cigarettes lifetime was determined by a self‐administered questionnaire. SNP associations modeled the effect of the minor allele additively on AMD using logistic regression, with adjustment for age, sex, and ever/never smoking. Joint effects of SNPs and smoking were examined comparing a null model containing only age, sex, and smoking against an extended model including genotypic and interaction terms. Genome‐wide significant main effects were detected at three known AMD loci: CFH (P = 7.51×10^?30), ARMS2 (P = 1.94×10^?23), and RDBP/CFB/C2 (P = 4.37×10^?10), while joint effects analysis revealed three genomic regions with P < 10^?5. Analyses stratified by smoking found genetic associations largely restricted to nonsmokers, with one notable exception: the chromosome 18q22.1 intergenic SNP rs17073641 (between SERPINB8 and CDH7), more strongly associated in nonsmokers (OR = 0.57, P = 2.73 × 10^?5), with an inverse association among smokers (OR = 1.42, P = 0.00228), suggesting that smoking modifies the effect of some genetic polymorphisms on AMD risk.     

Common genetic influences on depression,alcohol, and substance use disorders in Mexican‐American families

Multiple genetic and environmental factors influence the risk for both major depression and alcohol/substance use disorders. In addition, there is evidence that these illnesses share genetic factors. Although, the heritability of these illnesses is well established, relatively few studies have focused on ethnic minority populations. Here, we document the prevalence, heritability, and genetic correlations between major depression and alcohol and drug disorders in a large, community‐ascertained sample of Mexican‐American families. A total of 1,122 Mexican‐American individuals from 71 extended pedigrees participated in the study. All subjects received in‐person psychiatric interviews. Heritability, genetic, and environmental correlations were estimated using SOLAR. Thirty‐five percent of the sample met criteria for DSM‐IV lifetime major depression, 34% met lifetime criteria for alcohol use disorders, and 8% met criteria for lifetime drug use disorders. The heritability for major depression was estimated to be h² = 0.393 (P = 3.7 × 10^?6). Heritability estimates were higher for recurrent depression (h² = 0.463, P = 4.0 × 10^?6) and early onset depression (h² = 0.485, P = 8.5 × 10^?5). While the genetic correlation between major depression and alcohol use disorders was significant (ρ_g = 0.58, P = 7 × 10^?3), the environmental correlation between these traits was not significant. Although, there is evidence for increased rates of depression and substance use in US‐born individuals of Mexican ancestry, our findings indicate that genetic control over major depression and alcohol/substance use disorders in the Mexican‐American population is similar to that reported in other populations. © 2011 Wiley‐Liss, Inc.     

Microdeletions of ELP4 Are Associated with Language Impairment,Autism Spectrum Disorder,and Mental Retardation

Copy‐number variations (CNVs) are important in the aetiology of neurodevelopmental disorders and show broad phenotypic manifestations. We compared the presence of small CNVs disrupting the ELP4‐PAX6 locus in 4,092 UK individuals with a range of neurodevelopmental conditions, clinically referred for array comparative genomic hybridization, with WTCCC controls (n = 4,783). The phenotypic analysis was then extended using the DECIPHER database. We followed up association using an autism patient cohort (n = 3,143) compared with six additional control groups (n = 6,469). In the clinical discovery series, we identified eight cases with ELP4 deletions, and one with a partial duplication of ELP4 and PAX6. These cases were referred for neurological phenotypes including language impairment, developmental delay, autism, and epilepsy. Six further cases with a primary diagnosis of autism spectrum disorder (ASD) and similar secondary phenotypes were identified with ELP4 deletions, as well as another six (out of nine) with neurodevelopmental phenotypes from DECIPHER. CNVs at ELP4 were only present in 1/11,252 controls. We found a significant excess of CNVs in discovery cases compared with controls, P = 7.5 × 10^?3, as well as for autism, P = 2.7 × 10^?3. Our results suggest that ELP4 deletions are highly likely to be pathogenic, predisposing to a range of neurodevelopmental phenotypes from ASD to language impairment and epilepsy.     

The use of tetradecanoylphorbol acetate‐stimulated peripheral blood cells enhances the prognostic value of interphase fluorescence in situ hybridization in patients with chronic lymphocytic leukemia

Interphase fluorescence in situ hybridization (I‐FISH) studies have a remarkable prognostic value in patients with chronic lymphocytic leukemia (CLL). I‐FISH studies can be performed either on tetradecanoylphorbol acetate stimulated peripheral blood cells (I‐FISH‐TPA) or unstimulated peripheral blood mononuclear cells (I‐FISH‐PBMC). The aim of the study was to evaluate whether this finding was clinically relevant in a group of 235 patients with CLL. Fifty‐six patients had both I‐FISH‐TPA and I‐FISH‐PBMC results. Compared with uncultured cells, the cytogenetic detection rate rose from 57 to 80% with the use of TPA‐stimulated cells (P = 0.014). I‐FISH‐TPA provided a better prediction of treatment‐free survival compared with I‐FISH‐PBMC (P = 0.031 vs. 0.166). Then, I‐FISH‐PBMC results from 93 historical patients were compared with 86 recent patients with I‐FISH‐TPA results. Genomic aberrations were detected in 46 and 67% of patients from the I‐FISH‐PBMC and I‐FISH‐TPA cohorts, respectively. The detection rate of 13q deletion as the only aberration increased from 10% with I‐FISH‐PBMC to 37% with I‐FISH‐TPA (P = 0.006). In conclusion, I‐FISH‐TPA increased the detection rate of 13q deletion and had an improved prognostic value compared with I‐FISH‐PBMC. © 2009 Wiley‐Liss, Inc.     

Detection of chromothripsis‐like patterns with a custom array platform for chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a common disease with highly variable clinical course. Several recurrent chromosomal alterations are associated with prognosis and may guide risk‐adapted therapy. We have developed a targeted genome‐wide array to provide a robust tool for ascertaining abnormalities in CLL and to overcome limitations of the 4‐marker fluorescence in situ hybridization (FISH). DNA from 180 CLL patients were hybridized to the qChip®Hemo array with a high density of probes covering commonly altered loci in CLL (11q22‐q23, 13q14, and 17p13), nine focal regions (2p15‐p16.1, 2p24.3, 2q13, 2q36.3‐q37.1, 3p21.31, 8q24.21, 9p21.3, 10q24.32, and 18q21.32‐q21.33) and two larger regions (6q14.1‐q22.31 and 7q31.33‐q33). Overall, 86% of the cases presented copy number alterations (CNA) by array. There was a high concordance of array findings with FISH (84% sensitivity, 100% specificity); all discrepancies corresponded to subclonal alterations detected only by FISH. A chromothripsis‐like pattern was detected in eight cases. Three showed concomitant shattered 5p with gain of TERT along with isochromosome 17q. Presence of 11q loss was associated with shorter time to first treatment (P = 0.003), whereas 17p loss, increased genomic complexity, and chromothripsis were associated with shorter overall survival (P < 0.001, P = 0.001, and P = 0.02, respectively). In conclusion, we have validated a targeted array for the diagnosis of CLL that accurately detects, in a single experiment, all relevant CNAs, genomic complexity, chromothripsis, copy number neutral loss of heterozygosity, and CNAs not covered by the FISH panel. This test may be used as a practical tool to stratify CLL patients for routine diagnostics or clinical trials. © 2015 The Authors. Genes, Chromosomes & Cancer Published by Wiley Periodicals, Inc.     

Copy number variations could predict the outcome of bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma

We performed single nucleotide polymorphism (SNP) array analysis of 35 newly diagnosed symptomatic multiple myeloma (MM) patients who received bortezomib‐melphalan‐prednisone (VMP) to identify collaborating genetic events that could predict the outcome of treatment. A total of 340 copy number variations (CNVs) were identified, with the most frequently identified CNVs being gains on 1q, 19p, 9q, 3q, 9p, 15q, 19q, 5q, 11q, 5p, and 7q and losses on 1p, X, 13q, 14q, and 6q. The number and proportion of detected abnormalities by SNP array were associated with presence of cytogenetic abnormalities and complex karyotype. Moreover, increasing genomic complexity as ascertained by SNP arrays correlated with outcome of the VMP treatment. The frequency of CNVs was significantly different according to achievement of very good partial response (VGPR) to VMP treatment (<VGPR vs. ≥VGPR, median 11.7 vs. 7.7, respectively, P = 0.032) or occurrence of progressive disease (PD) after VMP treatment (progression vs. nonprogression, median 11.6 and 6.5, respectively, P = 0.011). The proportion of CNV length was also significantly higher in patients who did not achieve VGPR compared with those with ≥VGPR (median 31.9 vs. 19.6%, respectively, P = 0.004) and also higher in patients with PD compared with those without it (median 31.9 vs. 15.8%, respectively, P = 0.005). The patients who did not achieve VGPR tended to have deletion of 1p (P = 0.011) and gain of 3q (P = 0.05). Occurrence of PD was associated with complex karyotype (P = 0.020) and gain of 3q (P = 0.022). Our data show that the occurrence of CNVs correlates with clinical outcomes to first‐line VMP treatment. © 2014 Wiley Periodicals, Inc.     

CKS1B amplification is a frequent event in cutaneous squamous cell carcinoma with aggressive clinical behaviour

Genetic mechanisms giving rise to the development of cutaneous squamous cell carcinoma (cSCC) are poorly understood and development of genomic high resolution techniques has led to a better knowledge of the genetic basis of several human cancers. In this study, 16 cSCC were analyzed using array comparative genomic hybridization (arrayCGH). The most common aberrations found were gains of 3q11q13, 1q21.3q25, 13q34, and 19p13, and losses of 1p36p31, 3p24p21, 10p15q22, and 13q11q21. We detected gains (3/16) and amplification (1/16) of the 1q21.1q21.3 region. A potential candidate gene in this region, CKS1B (1q21.2), was selected for validation in an independent cohort and correlations with clinicopathological features were carried out. CKS1B gene and protein status were analyzed using fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) in a series of 53 cSCC, 22 actinic keratoses (AK), and 10 normal skin samples. cSCC presented a higher frequency of chromosome 1 polysomy than AK (70% vs. 46%, P = 0.047). Association between CKS1B protein overexpression and both polysomy and amplification was demonstrated in cSCC (P < 0.001). Regarding amplifications, 11 cSCC patients (21%) presented CKS1B gene amplification. Interestingly, 8/11 (73%) patients who showed a CKS1B amplification had presented metastatic spread (mcSCC). Differences between the presence of CKS1B amplification and the presence or absence of mcSCC were observed (mcSCC [8/14] vs. cSCC [3/39]) (P < 0.001). Several drugs targeting CKS1B have been reported and may be useful for treating patients with cSCC and CKS1B amplifications. © 2010 Wiley‐Liss, Inc.     

Gene‐based evaluation of low‐frequency variation and genetically‐predicted gene expression impacting risk of keloid formation

Keloids are benign dermal tumors occurring approximately 20 times more often in individuals of African descent as compared to individuals of European descent. While most keloids occur sporadically, a genetic predisposition is supported by both familial aggregation of some keloids and large differences in risk among populations. Despite Africans and African Americans being at increased risk over lighter‐skinned individuals, little genetic research exists into this phenotype. Using a combination of admixture mapping and exome analysis, we reported multiple common variants within chr15q21.2‐22.3 associated with risk of keloid formation in African Americans. Here we describe a gene‐based association analysis using 478 African American samples with exome genotyping data to identify genes containing low‐frequency variants associated with keloids, with evaluation of genetically‐predicted gene expression in skin tissues using association summary statistics. The strongest signal from gene‐based association was located in C15orf63 (P‐value = 6.6 × 10^?6) located at 15q15.3. The top result from gene expression was increased predicted DCAF4 expression (P‐value = 5.5 × 10^?4) in non–sun‐exposed skin, followed by increased predicted OR10A3 expression in sun‐exposed skin (P‐value = 6.9 × 10^?4). Our findings identify variation with putative roles in keloid formation, enhanced by the use of predicted gene expression to support the biological roles of variation identified only though genetic association studies.     

Genome-wide investigation identifies a rare copy-number variant burden associated with human spina bifida

PurposeNext-generation sequencing has implicated some risk variants for human spina bifida (SB), but the genome-wide contribution of structural variation to this complex genetic disorder remains largely unknown. We examined copy-number variant (CNV) participation in the genetic architecture underlying SB risk.MethodsA high-confidence ensemble approach to genome sequences (GS) was benchmarked and employed for systematic detection of common and rare CNVs in two separate ancestry-matched SB case–control cohorts.ResultsSB cases were enriched with exon disruptive rare CNVs, 44% of which were under 10 kb, in both ancestral populations (P = 6.75 × 10⁻⁷; P = 7.59 × 10⁻⁴). Genes containing these disruptive CNVs fall into molecular pathways, supporting a role for these genes in SB. Our results expand the catalog of variants and genes with potential contribution to genetic and gene–environment interactions that interfere with neurulation, useful for further functional characterization.ConclusionThis study underscores the need for genome-wide investigation and extends our previous threshold model of exonic, single-nucleotide variation toward human SB risk to include structural variation. Since GS data afford detection of CNVs with greater resolution than microarray methods, our results have important implications toward a more comprehensive understanding of the genetic risk and mechanisms underlying neural tube defect pathogenesis.     

Prognostic value of partial genetic instability in neuroblastoma with ≤50% neuroblastic cell content

Piqueras M, Navarro S, Cañete A, Castel V & Noguera R
(2011) Histopathology 59 , 22–30 Prognostic value of partial genetic instability in neuroblastoma with ≤50% neuroblastic cell content Aims: Better understanding of neuroblastoma genetics will improve with genome‐wide techniques. However, performing these analyses in samples with <60% neuroblast cells is not adequate. We evaluated the utility of fluorescence in situ hybridization (FISH) on tissue microarrays (TMA) in detecting partial genetic instability (PGI), focusing on samples with ≤50% neuroblast cells. Methods and results: Alterations of 11q and 17q were detected by FISH on 369 neuroblastoma samples in TMA. Status of the MYCN gene and 1p36 region has been established previously by FISH diagnosis. Partial genetic instability (PGI) was defined as the ratio between segmental genetic alterations detected and number of genetic markers diagnosed in each tumour. Of primary tumours, 14.6% harboured 11q deletions, whereas 42.6% showed 17q gain. PGI was established in 260 primary tumours, 67 of which contained ≤50% neuroblasts. Outcomes were statistically worse for patients whose tumours presented high PGI (P < 0.0001). Multivariate analysis revealed moderate and high PGI as prognostic factors. Conclusions: In the cohort examined in this study, univariate and multivariate analysis confirmed the effect of PGI in patient outcome. PGI established by FISH on TMA is a useful method to identify high‐risk patients even if tumours have a cell content of ≤50% neuroblast cells.     

A prognostic DNA signature for T1T2 node‐negative breast cancer patients

Predicting evolution of small node‐negative breast carcinoma is a real challenge in clinical practice. The aim of this study was to search whether qualitative or quantitative DNA changes may help to predict metastasis of small node‐negative breast carcinoma. Small invasive ductal carcinomas without axillary lymph node involvement (T1T2N0) from 168 patients with either good (111 patients with no event at 5 years after diagnosis) or poor (57 patients with early metastasis) outcome were analyzed with comparative genomic hybridization (CGH) array. A CGH classifier, identifying low‐ and high‐risk groups of metastatic recurrence, was established in a training set of 78 patients, then validated, and compared with clinicopathological parameters in a distinct set of 90 patients. The genomic status of regions located on 2p22.2, 3p23, and 8q21‐24 and the number of segmental alterations were defined in the training set to classify tumors into low‐ or high‐risk groups. In the validation set, in addition to estrogen receptors and grade, this CGH classifier provided significant prognostic information in multivariate analysis (odds ratio, 3.34; 95% confidence interval 1.01–11.02; P = 4.78 × 10^?2, Wald test). This study shows that tumor DNA contains important prognostic information that may help to predict metastasis in T1T2N0 tumors of the breast. © 2010 Wiley‐Liss, Inc.     

Genome‐wide analyses of psychological resilience in U.S. Army soldiers

Though a growing body of preclinical and translational research is illuminating a biological basis for resilience to stress, little is known about the genetic basis of psychological resilience in humans. We conducted genome‐wide association studies (GWASs) of self‐assessed (by questionnaire) and outcome‐based (incident mental disorders from predeployment to postdeployment) resilience among European (EUR) ancestry soldiers in the Army study to assess risk and resilience in servicemembers. Self‐assessed resilience (N = 11,492) was found to have significant common‐variant heritability (h² = 0.162, se = 0.050, p = 5.37 × 10^?4), and to be significantly negatively genetically correlated with neuroticism (r_g = ?0.388, p = .0092). GWAS results from the EUR soldiers revealed a genome‐wide significant locus on an intergenic region on Chr 4 upstream from doublecortin‐like kinase 2 (DCLK2) (four single nucleotide polymorphisms (SNPs) in LD; top SNP: rs4260523 [p = 5.65 × 10^?9] is an eQTL in frontal cortex), a member of the doublecortin family of kinases that promote survival and regeneration of injured neurons. A second gene, kelch‐like family member 36 (KLHL36) was detected at gene‐wise genome‐wide significance [p = 1.89 × 10^?6]. A polygenic risk score derived from the self‐assessed resilience GWAS was not significantly associated with outcome‐based resilience. In very preliminary results, genome‐wide significant association with outcome‐based resilience was found for one locus (top SNP: rs12580015 [p = 2.37 × 10^?8]) on Chr 12 downstream from solute carrier family 15 member 5 (SLC15A5) in subjects (N = 581) exposed to the highest level of deployment stress. The further study of genetic determinants of resilience has the potential to illuminate the molecular bases of stress‐related psychopathology and point to new avenues for therapeutic intervention.