A major quantitative trait locus for CD4-CD8 ratio is located on chromosome 11

CD4-CD8 ratio is an important diagnostic measure of immune system functioning. In particular, CD4-CD8 ratio predicts the time taken for progression of HIV infection to acquired immune deficiency syndrome (AIDS) and the long-term survival of AIDS patients. To map genes that regulate differences between healthy individuals in CD4-CD8 ratio, we typed 757 highly polymorphic microsatellite markers at an average spacing of similar to5 cM across the genome in 405 pairs of dizygotic twins at ages 12, 14 and 16. We used multipoint variance components linkage analysis to test for linkage between marker loci and CD4-CD8 ratio at each age. We found suggestive evidence of linkage on chromosome 11p in 12-year-old twins (LOD=2.55, P=0.00031) and even stronger evidence of linkage in the same region at age 14 (LOD 3.51, P=0.00003). Possible candidate genes include CD5 and CD6, which encode cell membrane proteins involved in the positive selection of thymocytes. We also found suggestive evidence of linkage at other areas of the genome including regions on chromosomes 1, 3, 4, 5, 6, 12, 13, 15, 17 and 22.

Quantitative Association Tests of Immune Responses to Antigens of Mycobacterium Tuberculosis: A Study of Twins in West Africa

There is now considerable evidence that host genetic factors are important in determining the outcome of infection with Mycobacterium tuberculosis (MTB). The aim of this study was to assess the role of several candidate genes in the variation observed in the immune responses to MTB antigens. In-vitro assays of T-cell proliferation, an in-vivo intradermal delayed hypersensitivity response; cytokine and antibody secretions to several mycobacterial peptide antigens were assessed in healthy, but exposed, West African twins. Candidate gene polymorphisms were typed in the NRAMP1, Vitamin D receptor, IL10, IL4, IL4 receptor and CTLA-4 genes. Variants of the loci IL10 (-1082 G/A), CTLA-4 (49 A/G) and the IL4 receptor (128 A/G) showed significant associations with immune responses to several antigens. T-cell proliferative responses and antibody responses were reduced, TNF-alpha responses were increased for subjects with the CTLA-4 G allele. The T-cell proliferative responses of subjects with IL10 GA and GG genotypes differed significantly. IL4 receptor AG and GG genotypes also showed significant differences in their T-cell proliferative responses to MTB antigens. These results yield a greater understanding of the genetic mechanisms that underlie the immune responses in tuberculosis and have implications for the design of therapeutic interventions.

Genetic screening for susceptibility to depression: can we and should we?

Objective: To summarize current knowledge about genetic susceptibility to mood disorders and examine ethical and policy issues that will need to be addressed if robustly replicated susceptibility alleles lead to proposals to screen and intervene with persons at increased genetic risk of developing mood disorders. Method: Empirical studies and reviews of the genetics of unipolar and bipolar depression were collected via MEDLINE and psycINFO database searches. Results: A number of candidate genes for depression have been identified, each of which increases the risk of mood disorders two- or threefold. None of the associations between these alleles and mood disorders have been consistently reported to date. Conclusions: Screening the population for genetic susceptibility to mood disorders is unlikely to be a practically useful policy (given plausible assumptions). Until there are effective treatments for persons at increased risk, screening is arguably unethical. Screening within affected families to advise on risks of developing depression would entail screening children and adolescents, raising potentially serious ethical issues of consent and stigmatization. Genetic research on depression should continue under appropriate ethical guidelines that protect the interests of research participants.

The policy and ethical implications of genetic research on attention deficit hyperactivity disorder

Objective: To review the policy and ethical implications of recent research on the molecular genetics of attention deficit hyperactivity disorder (ADHD). Method: MEDLINE and psycINFO database searches were used to identify studies on the genetics of ADHD. The implications of replicated candidate genes are discussed. Results: The findings for most genes have been inconsistent but several studies have implicated the genes in the dopaminergic pathway in the aetiology of ADHD. Conclusions: The current evidence on the genetics of ADHD is insufficient to justify genetic screening tests but it will provide important clues as to the aetiology of ADHD. Genetic information on susceptibility to ADHD has the potential to be abused and to stigmatize individuals. Researchers and clinicians need to be mindful of these issues in interpreting and disseminating the results of genetic studies of ADHD.

Polymorphisms in the trace amine receptor 4 (TRAR4) gene on chromosome 6q23.2 are associated with susceptibility to schizophrenia

Several linkage studies across multiple population groups provide convergent support for a susceptibility locus for schizophrenia - and, more recently, for bipolar disorder - on chromosome 6q13-q26. We genotyped 192 European-ancestry and African American (AA) pedigrees with schizophrenia from samples that previously showed linkage evidence to 6q13-q26, focusing on the MOXD1-STX7-TRARs gene cluster at 6q23.2, which contains a number of prime candidate genes for schizophrenia. Thirty-one screening single-nucleotide polymorphisms (SNPs) were selected, providing a minimum coverage of at least 1 SNP/20 kb. The association observed with rs4305745 (P = .0014) within the TRAR4 (trace amine receptor 4) gene remained significant after correction for multiple testing. Evidence for association was proportionally stronger in the smaller AA sample. We performed database searches and sequenced genomic DNA in a 30-proband subsample to obtain a high-density map of 23 SNPs spanning 21.6 kb of this gene. Single-SNP analyses and also haplotype analyses revealed that rs4305745 and/or two other polymorphisms in perfect linkage disequilibrium (LD) with rs4305745 appear to be the most likely variants underlying the association of the TRAR4 region with schizophrenia. Comparative genomic analyses further revealed that rs4305745 and/or the associated polymorphisms in complete LD with rs4305745 could potentially affect gene expression. Moreover, RT-PCR studies of various human tissues, including brain, confirm that TRAR4 is preferentially expressed in those brain regions that have been implicated in the pathophysiology of schizophrenia. These data provide strong preliminary evidence that TRAR4 is a candidate gene for schizophrenia; replication is currently being attempted in additional clinical samples.

The potential of microarrays to assist shrimp breeding and production: a review

The shrimp aquaculture industry is a relatively new livestock industry, having developed over the past 30 years. Thus, it is poised to take advantage of new technologies from the outset of selective breeding programs. This contrasts with long established livestock industries, where there are already highly specialised breeds. This review focuses specifically on the potential application of microarrays to shrimp breeding. Potential applications of microarrays in selective breeding programs are summarised. Microarrays can be used as a rapid means to generate molecular markers for genetic linkage mapping, and genetic maps have been constructed for yeast, Arabidopsis and barley using microarray technology. Microarrays can also be used in the hunt for candidate genes affecting particular traits, leading to development of perfect markers for these traits (i.e. causative mutations). However, this requires that microarray analysis be combined with genetic linkage mapping, and that substantial genomic information is available for the species in question. A novel application of microarrays is to treat gene expression as a quantitative trait in itself and to combine this with linkage mapping to identify quantitative trait loci controlling the levels of gene expression; this approach may identify higher level regulatory genes in specific pathways. Finally, patterns of gene expression observed using microarrays may themselves be treated as phenotypic traits in selection programs (e.g. a particular pattern of gene expression might be indicative of a disease tolerant individual). Microarrays are now being developed for a number of shrimp species in laboratories around the world, primarily with a focus on identifying genes involved in the immune response. However, at present, there is no central repository of shrimp genomic information, which limits the rate at which shrimp genomic research can be progressed. The application of microarrays to shrimp breeding will be extremely limited until there is a shared repository of genomic information for shrimp, and the collective will and resources to develop comprehensive genomic tools for shrimp.

Lack of association between genetic markers on chromosome 16q22-Q24 and type 1 diabetes in Russian affected families

Aim To evaluate whether the T1D susceptibility locus on chromosome 16q contributes to the genetic susceptibility to T1D in Russian patients. Method Thirteen microsatellite markers, spanning a 47-centimorgan genomic region on 16q22-q24 were evaluated for linkage to T1D in 98 Russian multiplex families. Multipoint logarithm of odds (LOD) ratio (MLS) and nonparametric LOD (NPL) values were computed for each marker, using GENEHUNTER 2.1 software. Four microsatellites (D16S422, D16S504, D16S3037, and D16S3098) and 6 biallelic markers in 2 positional candidate genes, ICSBP1 and NQO1, were additionally tested for association with T1D in 114 simplex families, using transmission disequilibrium test (TDT). Results A peak of linkage (MLS = 1.35, NPL = 0.91) was shown for marker D16S750, but this was not significant (P = 0.18). The subsequent linkage analysis in the subset of 46 multiplex families carrying a common risk HLA-DR4 haplotype increased peak MLS and NPL values to 1.77 and 1.22, respectively, but showed no significant linkage (P = 0.11) to T1D in the 16q22-q24 genomic region. TDT analysis failed to find significant association between these markers and disease, even after the conditioning for the predisposing HLA-DR4 haplotype. Conclusion Our results did not support the evidence for the susceptibility locus to T1D on chromosome 16q22-24 in the Russian family data set. The lack of association could reflect genetic heterogeneity of type 1 diabetes in diverse ethnic groups.

Expression of HOXB2, a retinoic acid signaling target in pancreatic cancer and pancreatic intraepithelial neoplasia

Purpose: Despite significant progress in understanding the molecular pathology of pancreatic cancer and its precursor lesion: pancreatic intraepithelial neoplasia (PanIN), there remain no molecules with proven clinical utility as prognostic or therapeutic markers. Here, we used oligonucleotide microarrays to interrogate mRNA expression of pancreatic cancer tissue and normal pancreas to identify novel molecular pathways dysregulated in the development and progression of pancreatic cancer. Experimental Design: RNA was hybridized to Affymetrix Genechip HG-U133 oligonucleotide microarrays. A relational database integrating data from publicly available resources was created to identify candidate genes potentially relevant to pancreatic cancer. The protein expression of one candidate, homeobox B2 (HOXB2), in PanIN and pancreatic cancer was assessed using immunohistochemistry. Results: We identified aberrant expression of several components of the retinoic acid (RA) signaling pathway (RARa, MUC4, Id-1, MMP9, uPAR, HB-EGF, HOXB6, and HOXB2), many of which are known to be aberrantly expressed in pancreatic cancer and Pan IN. HOXB2, a downstream target of RA, was up-regulated 6.7-fold in pancreatic cancer compared with normal pancreas. Immunohistochemistry revealed ectopic expression of HOXB2 in 15% of early Pan IN lesions and 48 of 128 (38%) pancreatic cancer specimens. Expression of HOXB2 was associated with nonresectable tumors and was an independent predictor of poor survival in resected tumors. Conclusions: We identified aberrant expression of RA signaling components in pancreatic cancer, including HOXB2, which was expressed in a proportion of PanIN lesions. Ectopic expression of HOXB2 was associated with a poor prognosis for all patients with pancreatic cancer and was an independent predictor of survival in patients who underwent resection.

Genome-wide scan of IQ finds significant linkage to a quantitative trait locus on 2q

A genome-wide linkage scan of 795 microsatellite markers (761 autosomal, 34 X chromosome) was performed on Multidimensional Aptitude Battery subtests and verbal, performance and full scale scores, the WAIS-R Digit Symbol subtest, and two word-recognition tests (Schonell Graded Word Reading Test, Cambridge Contextual Reading Test) highly predictive of IQ. The sample included 361 families comprising 2-5 siblings who ranged in age from 15.7 to 22.2 years; genotype, but not phenotype, data were available for 81% of parents. A variance components analysis which controlled for age and sex effects showed significant linkage for the Cambridge reading test and performance IQ to the same region on chromosome 2, with respective LOD scores of 4.15 and 3.68. Suggestive linkage (LOD score > 2.2) for various measures was further supported on chromosomes 6, 7, 11, 14, 21 and 22. Where location of linkage peaks converged for IQ subtests within the same scale, the overall scale score provided increased evidence for linkage to that region over any individual subtest. Association studies of candidate genes, particularly those involved in neural transmission and development, will be directed to genes located under the linkage peaks identified in this study.

Genome-wide linkage scan for loci influencing plasma triglycerides

Background: Plasma triglyceride concentration is known to be a significant risk factor for cardiovascular disease (CVD). Previous studies have found that the level of triglycerides is strongly influenced by genetic factors. Methods: To identify quantitative trait loci influencing triglycerides, we conducted a genome-wide linkage scan on data from 485 Australian adult dizygotic twin pairs. Prior to linkage analysis, triglyceride values were adjusted for the effects of covariates including age, sex, time since last meal, time of blood collection (CT) and time to plasma separation. Results: The heritability estimate for ln(triglyceride) adjusted for all above fixed effects was 0.49. The highest multipoint LOD score observed was 2.94 (genome-wide p=0.049) on chromosome 7 (at 65cM). This 7p region contains several candidate genes. Two other regions with suggestive multipoint LOD scores were also identified on chromosome 4 (LOD score=2.26 at 62cM) and chromosome X (LOD score=2.01 at 81cM). Conclusions: The linkage peaks found represent newly identified regions for more detailed study, in particular the significant linkage observed on chromosome 7p13. \ (c) 2006 Elsevier B.V. All rights reserved.

Genetic and environmental influences on dentofacial structures and oral health: studies of Australian twins and their families

Our studies of the teeth and faces of Australian twins commenced at the School of Dentistry, The University of Adelaide in the early 1980s. There are now over 900 pairs of twins enrolled in our continuing investigations, together with 1200 relatives. There are 3 main cohorts of participants. The first cohort comprises around 300 pairs of teenage twins for whom various records have been collected, including dental casts, facial photographs, finger and palm prints and information on laterality, including handedness. The second cohort comprises around 300 pairs of twins who have been examined at 3 stages of dental development from approximately 4 years of age to about 14 years: at primary, mixed, and permanent dentition (excluding 3rd molars) stages. The most recent study of tooth emergence and oral health, for which we are currently recruiting twins, will provide a third cohort of around 500 twin pairs aged from around birth to 3 to 4 years of age. Our broad aim in these studies has been to improve our understanding of how genetic and environmental factors contribute to variation in dental and facial features, and to oral health. We have also used our data to investigate aspects of the determination of laterality, particularly the fascinating phenomenon of mirror imaging. We plan to maximize the use of the longitudinal data and DNA we have collected, and continue to collect, by performing genome-wide scans for putative genetic linkage peaks for a range of dental features, and then to test for association between a series of likely candidate genes and our phenotypes.

Further evidence of linkage at 7p22 with familial hyperaldosteronism type II

Primary aldosteronism (PAL) is caused by the autonomous over-production of aldosterone. Once thought rare, it is now reported to be responsible for 5–10% of hypertension. Familial hyperaldosteronism type II (FH-II), unlike familial hyperaldosteronism type I, is not glucocorticoid-remediable and not associated with the hybrid CYP11B1/CYP11B2 gene mutation. At least five times more common than FH-I, FH-II is clinically, biochemically and morphologically indistinguishable from apparently sporadic PAL, suggesting that its incidence maybe even higher. Studies performed in collaboration with C Stratakis (NIH, Bethesda) on our largest Australian FH-II family (eight affected members) demonstrated linkage at chromosome 7p22. Similar linkage at this region was also found in a South American FH-II family (DNA provided by MI New, Presbyterian Hospital, New York). Mutations in the exons and intron/exon boundaries of the PRKARIB gene (which resides at 7p22 and is closely related to PRKARIA gene mutated in Carney complex) have been excluded in our largest Australian FH-II family. Using more finely spaced markers, we have confirmed linkage at 7p22 in these 2 families, and identified a second Australian family with evidence of linkage at this locus. The combined multipoint LOD score for these 3 families is 4.87 (θ=0) with markers D7S462 and D7S2424, which exceeds the critical threshold for genome-wide significance suggested by Lander and Kruglyak (1995), providing strong support for this locus harbouring mutations responsible for FH-II. A newly identified recombination event in our largest Australian family has narrowed the region of linkage by 1.8 Mb, permitting exclusion of approximately half the genes residing in the original reported 5Mb linked locus. In addition, we have strongly excluded linkage to these key markers in two Australian families (maximum multipoint LOD scores −3.51 and −2.77), supporting the notion that FH-II may be genetically heterogeneous. In order to identify candidate genes at 7p22, more closely spaced markers will be used to refine the locus, as well as single nucleotide polymorphism analysis.

Further evidence of linkage at 7p22 with familial hyperaldosteronism type II and exclusion of genetic defects in the RBAK coding regions

Once thought rare, primary aldosteronism (PAL) is now reported to be responsible for 5–10% of hypertension. Unlike familial hyperaldosteronism type I (FH-I), FH-II is not glucocorticoidremediable and not associated with the hybrid CYP11B1/CYP11B2 gene mutation. At least five times more common than FH-I, FH-II is clinically indistinguishable from apparently sporadic PAL, suggesting an even higher incidence. Studies performed in collaboration with C Stratakis (NIH, Bethesda) on our largest Australian family (eight affected members) demonstrated linkage at chromosome 7p22. Linkage at this region was also found in a South American family (DNA provided by MI New, Mount Sinai School of Medicine, New York) and in a second Australian family. The combined multipoint LOD score for these 3 families is 4.61 (q = 0) with markers D7S462 and D7S517, providing strong support for this locus harbouring mutations responsible for FH-II. A newly identified recombination event in our largest Australian family has narrowed the region of linkage by 1.8 Mb, permitting exclusion of approximately half the genes residing in the originally reported 5 Mb linked locus. Candidate genes that are involved in cell cycle control are of interest as adrenal hyperplasia and adrenal adenomas are common in FH-II patients. A novel candidate gene in this linked region produces the retinoblastoma-associated Kruppel-associated box protein (RBaK) which interacts with the retinoblastoma gene product to repress the expression of genes activated by members of the E2F family of transcription factors.

Dopamine, empathy and the neurobiology of leadership

Objectives: Organisational Psychologists have long sought after methods by which to train individuals to become more effective leaders. Indeed considerable sums of money are spent on the design of such training programs. Yet it is not clear whether or not leadership skills can be taught or whether they are innate. Social leadership is a varied construct consisting of many diverse aspects, yet the ability to empathise with subordinates is a core skill that underpins effective transformational leadership. This type of leadership consists of four characteristics which are labelled ‘idealized influence’, ‘inspirational motivation’, ‘intellectual stimulation’ and ‘individualized consideration’. This is distinct from the transactional style of leadership, which is based on offering contingent rewards for completion of specific tasks. By identifying a specific gene that mediates distinct leadership traits, more effective training regimes can be designed. Design: There are two likely candidate genes that may mediate empathic leadership. The first is catechol-O-methyltransferase (COMT) which is involved with dopamine synthesis, and the second is the serotonin transporter promoter gene (5-HTTLPR). Both these genes mostly appear in the general population in their heterozygotic form. Thus by comparing phenotypes in leadership traits a measure of base line differences can be examined. Methods: 115 volunteers completed the Multifactor Leadership questionnaire (MLQ), which is a standard 12-item leadership psychometric scale and also underwent buccal swab for subsequent genotyping. Results: Of the 115 subjects 37 were heterozygotic for the COMT gene and 47 heterozygotic for 5-HTTLPR. Of the 12 MLQ subscales, the scores for two of the subscales only differed between the two participant groups. Individuals who were heterozygotic for the COMT gene scored higher on the ‘Inspirational motivation’ t(84)=1.99, p=0.05 and ‘Intellectual stimulation’ t(82)=1.94, p=0.05 scales compared to the carriers for the heterozygotic 5HTPP gene. Conclusions: Given that the behaviours described by these two MLQ subscales require leaders to empathise with subordinates, the current results suggest that dopamine may play a role in this important social task. The fact that both heterozygotic carriers for COMT and 5HTPP were compared allows a comparison to be made between the genotypes most prevalent in the general population.

Genome-wide association analysis identifies novel loci for chronotype in 100,420 individuals from the UK Biobank

Our sleep timing preference, or chronotype, is a manifestation of our internal biological clock. Variation in chronotype has been linked to sleep disorders, cognitive and physical performance, and chronic disease. Here we perform a genome-wide association study of self-reported chronotype within the UK Biobank cohort (n=100,420). We identify 12 new genetic loci that implicate known components of the circadian clock machinery and point to previously unstudied genetic variants and candidate genes that might modulate core circadian rhythms or light-sensing pathways. Pathway analyses highlight central nervous and ocular systems and fear-response-related processes. Genetic correlation analysis suggests chronotype shares underlying genetic pathways with schizophrenia, educational attainment and possibly BMI. Further, Mendelian randomization suggests that evening chronotype relates to higher educational attainment. These results not only expand our knowledge of the circadian system in humans but also expose the influence of circadian characteristics over human health and life-history variables such as educational attainment.