Serum bilirubin concentration is modified by UGT1A1 haplotypes and influences risk of type-2 diabetes in the Norfolk Island genetic isolate.

BACKGROUND: Located in the Pacific Ocean between Australia and New Zealand, the unique population isolate of Norfolk Island has been shown to exhibit increased prevalence of metabolic disorders (type-2 diabetes, cardiovascular disease) compared to mainland Australia. We investigated this well-established genetic isolate, utilising its unique genomic structure to increase the ability to detect related genetic markers. A pedigree-based genome-wide association study of 16 routinely collected blood-based clinical traits in 382 Norfolk Island individuals was performed. RESULTS: A striking association peak was located at chromosome 2q37.1 for both total bilirubin and direct bilirubin, with 29 SNPs reaching statistical significance (P < 1.84 × 10(-7)). Strong linkage disequilibrium was observed across a 200 kb region spanning the UDP-glucuronosyltransferase family, including UGT1A1, an enzyme known to metabolise bilirubin. Given the epidemiological literature suggesting negative association between CVD-risk and serum bilirubin we further explored potential associations using stepwise multivariate regression, revealing significant association between direct bilirubin concentration and type-2 diabetes risk. In the Norfolk Island cohort increased direct bilirubin was associated with a 28% reduction in type-2 diabetes risk (OR: 0.72, 95% CI: 0.57-0.91, P = 0.005). When adjusted for genotypic effects the overall model was validated, with the adjusted model predicting a 30% reduction in type-2 diabetes risk with increasing direct bilirubin concentrations (OR: 0.70, 95% CI: 0.53-0.89, P = 0.0001). CONCLUSIONS: In summary, a pedigree-based GWAS of blood-based clinical traits in the Norfolk Island population has identified variants within the UDPGT family directly associated with serum bilirubin levels, which is in turn implicated with reduced risk of developing type-2 diabetes within this population.

QTL-based association analyses reveal novel genes influencing pleiotropy of metabolic syndrome (MetS).

OBJECTIVE: Metabolic Syndrome (MetS) is a phenotype cluster predisposing to type 2 diabetes and cardiovascular disease. We conducted a study to elucidate the genetic basis underlying linkage signals for multiple representative traits of MetS that we had previously identified at two significant QTLs on chromosomes 3q27 and 17p12. DESIGN AND METHODS: We performed QTL-specific genomic and transcriptomic analyses in 1,137 individuals from 85 extended families that contributed to the original linkage. We tested in SOLAR association of MetS phenotypes with QTL-specific haplotype-tagging SNPs as well as transcriptional profiles of peripheral blood mononuclear cells (PBMCs). RESULTS: SNPs significantly associated with MetS phenotypes under the prior hypothesis of linkage mapped to seven genes at 3q27 and seven at 17p12. Prioritization based on biologic relevance, SNP association, and expression analyses identified two genes: insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) at 3q27 and tumor necrosis factor receptor 13B (TNFRSF13B) at 17p12. Prioritized genes could influence cell-cell adhesion and adipocyte differentiation, insulin/glucose responsiveness, cytokine effectiveness, plasma lipid levels, and lipoprotein densities. CONCLUSIONS: Using an approach combining genomic, transcriptomic, and bioinformatic data we identified novel candidate genes for MetS.

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 h(2) = 0.393 (P = 3.7 × 10(-6)). Heritability estimates were higher for recurrent depression (h(2) = 0.463, P = 4.0 × 10(-6)) and early onset depression (h(2) = 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.

Impact of DISC1 variation on neuroanatomical and neurocognitive phenotypes.

Although disrupted in schizophrenia 1 (DISC1) has been implicated in many psychiatric disorders, including schizophrenia, bipolar disorder, schizoaffective disorder and major depression, its biological role in these disorders is unclear. To better understand this gene and its role in psychiatric disease, we conducted transcriptional profiling and genome-wide association analysis in 1232 pedigreed Mexican-American individuals for whom we have neuroanatomic images, neurocognitive assessments and neuropsychiatric diagnoses. SOLAR was used to determine heritability, identify gene expression patterns and perform association analyses on 188 quantitative brain-related phenotypes. We found that the DISC1 transcript is highly heritable (h(2)=0.50; P=1.97 × 10(-22)), and that gene expression is strongly cis-regulated (cis-LOD=3.89) but is also influenced by trans-effects. We identified several DISC1 polymorphisms that were associated with cortical gray matter thickness within the parietal, temporal and frontal lobes. Associated regions affiliated with memory included the entorhinal cortex (rs821639, P=4.11 × 10(-5); rs2356606, P=4.71 × 10(-4)), cingulate cortex (rs16856322, P=2.88 × 10(-4)) and parahippocampal gyrus (rs821639, P=4.95 × 10(-4)); those affiliated with executive and other cognitive processing included the transverse temporal gyrus (rs9661837, P=5.21 × 10(-4); rs17773946, P=6.23 × 10(-4)), anterior cingulate cortex (rs2487453, P=4.79 × 10(-4); rs3738401, P=5.43 × 10(-4)) and medial orbitofrontal cortex (rs9661837; P=7.40 × 10(-4)). Cognitive measures of working memory (rs2793094, P=3.38 × 10(-4)), as well as lifetime history of depression (rs4658966, P=4.33 × 10(-4); rs12137417, P=4.93 × 10(-4)) and panic (rs12137417, P=7.41 × 10(-4)) were associated with DISC1 sequence variation. DISC1 has well-defined genetic regulation and clearly influences important phenotypes related to psychiatric disease.

Genetic control over the resting brain.

The default-mode network, a coherent resting-state brain network, is thought to characterize basal neural activity. Aberrant default-mode connectivity has been reported in a host of neurological and psychiatric illnesses and in persons at genetic risk for such illnesses. Whereas the neurophysiologic mechanisms that regulate default-mode connectivity are unclear, there is growing evidence that genetic factors play a role. In this report, we estimate the importance of genetic effects on the default-mode network by examining covariation patterns in functional connectivity among 333 individuals from 29 randomly selected extended pedigrees. Heritability for default-mode functional connectivity was 0.424 +/- 0.17 (P = 0.0046). Although neuroanatomic variation in this network was also heritable, the genetic factors that influence default-mode functional connectivity and gray-matter density seem to be distinct, suggesting that unique genes influence the structure and function of the network. In contrast, significant genetic correlations between regions within the network provide evidence that the same genetic factors contribute to variation in functional connectivity throughout the default mode. Specifically, the left parahippocampal region was genetically correlated with all other network regions. In addition, the posterior cingulate/precuneus region, medial prefrontal cortex, and right cerebellum seem to form a subnetwork. Default-mode functional connectivity is influenced by genetic factors that cannot be attributed to anatomic variation or a single region within the network. By establishing the heritability of default-mode functional connectivity, this experiment provides the obligatory evidence required before these measures can be considered as endophenotypes for psychiatric or neurological illnesses or to identify genes influencing intrinsic brain function.

INSIG1 influences obesity-related hypertriglyceridemia in humans.

In our analysis of a quantitative trait locus (QTL) for plasma triglyceride (TG) levels [logarithm of odds (LOD) = 3.7] on human chromosome 7q36, we examined 29 single nucleotide polymorphisms (SNPs) across INSIG1, a biological candidate gene in the region. Insulin-induced genes (INSIGs) are feedback mediators of cholesterol and fatty acid synthesis in animals, but their role in human lipid regulation is unclear. In our cohort, the INSIG1 promoter SNP rs2721 was associated with TG levels (P = 2 x 10(-3) in 1,560 individuals of the original linkage cohort, P = 8 x 10(-4) in 920 unrelated individuals of the replication cohort, combined P = 9.9 x 10(-6)). Individuals homozygous for the T allele had 9% higher TG levels and 2-fold lower expression of INSIG1 in surgical liver biopsy samples when compared with individuals homozygous for the G allele. Also, the T allele showed additional binding of nuclear proteins from HepG2 liver cells in gel shift assays. Finally, the variant rs7566605 in INSIG2, the only homolog of INSIG1, enhances the effect of rs2721 (P = 0.00117). The variant rs2721 alone explains 5.4% of the observed linkage in our cohort, suggesting that additional, yet-undiscovered genes and sequence variants in the QTL interval also contribute to alterations in TG levels in humans.

Polymorphisms of the VDR gene are associated with presence of solar keratoses on the skin.

BACKGROUND: Vitamin D has a range of biological effects including antiproliferative functions that are mediated through its receptors, encoded by the VDR gene. OBJECTIVES: We investigated polymorphisms within the VDR gene for association with solar keratosis (SK), a biomarker for skin cancer, and examined interactions with skin phenotype. METHODS: Among participants of the community-based Nambour Skin Cancer Study, we genotyped 190 people with SKs and 190 without for ApaI, TaqI and FokI polymorphisms. RESULTS: We found a significant difference in genotype frequencies of the TaqI polymorphism between affected and unaffected populations (P = 0.008). The TT/tt genotype group was associated with a twofold increase in odds of being affected by one or more SK. Individuals with fair skin and the TT/tt genotype had about a sevenfold increase, whereas fair-skinned people with the Tt genotype had a fourfold increase in odds of being affected by SK. Individuals with the TT/tt genotype who were prone to burn and not tan on acute sun exposure had about a sixfold increase in odds of SK. Fair-skinned people with VDR-Apa AA/aa genotypes had about an eightfold increase in odds of being affected by SK compared with a fivefold increase in individuals with the Aa genotype and fair skin. CONCLUSIONS: The trend for homozygote genotypes to increase the odds of SK suggests that intermediate VDR activity is important in protection or that the heterodimer formed by a heterozygous genotype may have an altered binding potential. Overall, these analyses indicate that VDR may be important in SK development.

Association analysis of somatostatin receptor (SSTR1 and SSTR2) polymorphisms in breast cancer and solar keratosis.

The presence of somatostatin receptors (SSTR1-5) in tumour cells indicates a potential for somatostatin to bind and suppress growth, as well as allowing for therapeutic treatment with somatostatin analogues. The genes for SSTR1 and SSTR2 have been shown to contain dinucleotide repeat polymorphisms. We have performed association studies on breast cancer and solar keratosis populations to determine whether these genes play a role in the development of these conditions. Results showed that there was no significant difference between SSTR1 and SSTR2 polymorphism frequencies in the tested breast cancer population (P = 0.59 and P = 0.54, respectively) nor the solar keratosis population (P = 0.10 and P = 0.883, respectively) as compared to unaffected populations. Hence, these studies do not support a role for these receptor genes in either breast cancer or solar keratosis lesions.