Obesity and obesogenic growth are both highly heritable and modified by diet in a nonhuman primate model, the African green monkey (Chlorocebus aethiops sabaeus).

OBJECTIVE: In humans, the ontogeny of obesity throughout the life course and the genetics underlying it has been historically difficult to study. We compared, in a non-human primate model, the lifelong growth trajectories of obese and non-obese adults to assess the heritability of and map potential genomic regions implicated in growth and obesity. STUDY POPULATION: A total of 905 African green monkeys, or vervets (Chlorocebus aethiops sabaeus) (472 females, 433 males) from a pedigreed captive colony. METHODS: We measured fasted body weight (BW), crown-to-rump length (CRL), body-mass index (BMI) and waist circumference (WC) from 2000 to 2015. We used a longitudinal clustering algorithm to detect obesogenic growth, and logistic growth curves implemented in nonlinear mixed effects models to estimate three growth parameters. We used maximum likelihood variance decomposition methods to estimate the genetic contributions to obesity-related traits and growth parameters, including a test for the effects of a calorie-restricted dietary intervention. We used multipoint linkage analysis to map implicated genomic regions. RESULTS: All measurements were significantly influenced by sex, and with the exception of WC, also influenced by maternal and post-natal diet. Chronic obesity outcomes were significantly associated with a pattern of extended growth duration with slow growth rates for BW. After accounting for environmental influences, all measurements were found to have a significant genetic component to variability. Linkage analysis revealed several regions suggested to be linked to obesity-related traits that are also implicated in human obesity and metabolic disorders. CONCLUSIONS: As in humans, growth patterns in vervets have a significant impact on adult obesity and are largely under genetic control with some evidence for maternal and dietary programming. These results largely mirror findings from human research, but reflect shorter developmental periods, suggesting that the vervet offers a strong genetic model for elucidating the ontogeny of human obesity.

Genome-wide association study of Tourette's syndrome.

Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P<5 × 10(-8)); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (P=1.85 × 10(-6)). A secondary analysis including an additional 211 cases and 285 controls from two closely related Latin American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (P=3.6 × 10(-7) for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder.

A genome-wide meta-analysis of association studies of Cloninger's Temperament Scales.

Temperament has a strongly heritable component, yet multiple independent genome-wide studies have failed to identify significant genetic associations. We have assembled the largest sample to date of persons with genome-wide genotype data, who have been assessed with Cloninger's Temperament and Character Inventory. Sum scores for novelty seeking, harm avoidance, reward dependence and persistence have been measured in over 11,000 persons collected in four different cohorts. Our study had >80% power to identify genome-wide significant loci (P<1.25 × 10(-8), with correction for testing four scales) accounting for ≥0.4% of the phenotypic variance in temperament scales. Using meta-analysis techniques, gene-based tests and pathway analysis we have tested over 1.2 million single-nucleotide polymorphisms (SNPs) for association to each of the four temperament dimensions. We did not discover any SNPs, genes, or pathways to be significantly related to the four temperament dimensions, after correcting for multiple testing. Less than 1% of the variability in any temperament dimension appears to be accounted for by a risk score derived from the SNPs showing strongest association to the temperament dimensions. Elucidation of genetic loci significantly influencing temperament and personality will require potentially very large samples, and/or a more refined phenotype. Item response theory methodology may be a way to incorporate data from cohorts assessed with multiple personality instruments, and might be a method by which a large sample of a more refined phenotype could be acquired.

Change in mandibular trabecular pattern and hip fracture rate in elderly women.

OBJECTIVES: To determine if alterations of trabecular pattern, or the rate of change of jaw trabeculae, are associated with rate of hip fracture. METHODS: Participants in a population-based study of residents of a California retirement community (Leisure World Cohort Study) were asked for permission to obtain their dental radiographs. Periapical radiographs were retrieved on 598 women (average age at time of first radiograph=77 years). Several measurements of trabecular pattern (strut analysis), textural properties (run-length analysis) and Fourier analysis were made in several anatomical regions of the jaw. These trabecular features and clinical information self-reported by subjects in the early 1980s were examined for association with hip fracture rate using Cox proportional-hazard regression. RESULTS: Rate of hip fracture increased with decreasing average length of node-to-terminus struts in the mandibular incisor region. Each 0.01 mm per year decrease in the average length of node-to-terminus struts increased hip fracture rate by a factor of 2.9 (P=0.02, accuracy=73%). Inclusion of clinical parameters improved the predictive model compared with use of the radiographic parameter alone (accuracy=79%). Similar results were seen for percent change per year in this parameter. CONCLUSIONS: Changes in radiographic trabecular structure, augmented with clinical information, are predictive of hip fracture in elderly women. Further refinement of both the radiographic and clinical parameters may lead to a screening process accessible to a large number of women and to early diagnosis and treatment of osteoporosis.

Fine-scale mapping of a locus for severe bipolar mood disorder on chromosome 18p11.3 in the Costa Rican population.

We have searched for genes predisposing to bipolar disorder (BP) by studying individuals with the most extreme form of the affected phenotype, BP-I, ascertained from the genetically isolated population of the Central Valley of Costa Rica (CVCR). The results of a previous linkage analysis on two extended CVCR BP-I pedigrees, CR001 and CR004, and of linkage disequilibrium (LD) analyses of a CVCR population sample of BP-I patients implicated a candidate region on 18p11.3. We further investigated this region by creating a physical map and developing 4 new microsatellite and 26 single-nucleotide polymorphism markers for typing in the pedigree and population samples. We report the results of fine-scale association analyses in the population sample, as well as evaluation of haplotypes in pedigree CR001. Our results suggest a candidate region containing six genes but also highlight the complexities of LD mapping of common disorders.

Hereditary vascular retinopathy, cerebroretinal vasculopathy, and hereditary endotheliopathy with retinopathy, nephropathy, and stroke map to a single locus on chromosome 3p21.1-p21.3.

We performed a genomewide search for linkage in an extended Dutch family with hereditary vascular retinopathy associated with migraine and Raynaud phenomenon. Patients with vascular retinopathy are characterized by microangiopathy of the retina, accompanied by microaneurysms and telangiectatic capillaries. The genome search, using a high throughput capillary sequencer, revealed significant evidence of linkage to chromosome 3p21.1-p21.3 (maximum pairwise LOD score 5.25, with D3S1578). Testing of two additional families that had a similar phenotype, cerebroretinal vasculopathy, and hereditary endotheliopathy with retinopathy, nephropathy, and stroke, revealed linkage to the same chromosomal region (combined maximum LOD score 6.30, with D3S1588). Haplotype analysis of all three families defined a 3-cM candidate region between D3S1578 and D3S3564. Our study shows that three autosomal dominant vasculopathy syndromes with prominent cerebroretinal manifestations map to the same 3-cM interval on 3p21, suggesting a common locus.

Genome screening for linkage disequilibrium in a Costa Rican sample of patients with bipolar-I disorder: a follow-up study on chromosome 18.

Linkage disequilibrium (LD) methods offer great promise for mapping complex traits, but have thus far been applied sparingly. In this paper we describe an LD mapping study of severe bipolar disorder (BP-I) in the genetically isolated population of the Central Valley of Costa Rica. This study provides the first complete screen of a chromosome for a complex trait using LD mapping and presents the first application of a new LD mapping statistic (ancestral haplotype reconstruction (AHR)) that evaluates haplotype sharing among affected individuals. The results of this chromosome-wide analysis are instructive for genome-wide LD mapping in isolated populations. Furthermore, the analysis continues to support a possible BP-I locus on 18pter, suggested by previous analyses in this population. Evidence for a possible BP-I locus on 18q12.2 is also described.

Screening a large reference sample to identify very low frequency sequence variants: comparisons between two genes.

Most human sequence variation is in the form of single-nucleotide polymorphisms (SNPs). It has been proposed that coding-region SNPs (cSNPs) be used for direct association studies to determine the genetic basis of complex traits. The success of such studies depends on the frequency of disease-associated alleles, and their distribution in different ethnic populations. If disease-associated alleles are frequent in most populations, then direct genotyping of candidate variants could show robust associations in manageable study samples. This approach is less feasible if the genetic risk from a given candidate gene is due to many infrequent alleles. Previous studies of several genes demonstrated that most variants are relatively infrequent (<0.05). These surveys genotyped small samples (n<75) and thus had limited ability to identify rare alleles. Here we evaluate the prevalence and distribution of such rare alleles by genotyping an ethnically diverse reference sample that is more than six times larger than those used in previous studies (n=450). We screened for variants in the complete coding sequence and intron-exon junctions of two candidate genes for neuropsychiatric phenotypes: SLC6A4, encoding the serotonin transporter; and SLC18A2, encoding the vesicular monoamine transporter. Both genes have unique roles in neuronal transmission, and variants in either gene might be associated with neurobehavioral phenotypes.

The genome-wide distribution of background linkage disequilibrium in a population isolate.

Recent interest in using association studies to investigate complex traits has focused attention on understanding linkage disequilibrium (LD) in the human genome. We examined the genome-wide distribution and magnitude of such background LD (BLD) using 1036 densely spaced microsatellites, in a sample from the demographically well characterized population of the Central Valley of Costa Rica. High levels of BLD were found between linked markers several centiMorgans apart, and although BLD was significantly related to genetic distance between markers it was not spread uniformly throughout the genome. Understanding the forces governing the distribution of BLD in the genome will require similar investigations using a standard set of markers in other populations.

Linkage analysis of a complex pedigree with severe bipolar disorder, using a Markov chain Monte Carlo method.

Recently developed algorithms permit nonparametric linkage analysis of large, complex pedigrees with multiple inbreeding loops. We have used one such algorithm, implemented in the package SimWalk2, to reanalyze previously published genome-screen data from a Costa Rican kindred segregating for severe bipolar disorder. Our results are consistent with previous linkage findings on chromosome 18 and suggest a new locus on chromosome 5 that was not identified using traditional linkage analysis.

Familial aggregation of absolute pitch.

Absolute pitch (AP) is a behavioral trait that is defined as the ability to identify the pitch of tones in the absence of a reference pitch. AP is an ideal phenotype for investigation of gene and environment interactions in the development of complex human behaviors. Individuals who score exceptionally well on formalized auditory tests of pitch perception are designated as "AP-1." As described in this report, auditory testing of siblings of AP-1 probands and of a control sample indicates that AP-1 aggregates in families. The implications of this finding for the mapping of loci for AP-1 predisposition are discussed.

Assessing the feasibility of linkage disequilibrium methods for mapping complex traits: an initial screen for bipolar disorder loci on chromosome 18.

Linkage disequilibrium (LD) analysis has been promoted as a method of mapping disease genes, particularly in isolated populations, but has not yet been used for genome-screening studies of complex disorders. We present results of a study to investigate the feasibility of LD methods for genome screening using a sample of individuals affected with severe bipolar mood disorder (BP-I), from an isolated population of the Costa Rican central valley. Forty-eight patients with BP-I were genotyped for markers spaced at approximately 6-cM intervals across chromosome 18. Chromosome 18 was chosen because a previous genome-screening linkage study of two Costa Rican families had suggested a BP-I locus on this chromosome. Results of the current study suggest that LD methods will be useful for mapping BP-I in a larger sample. The results also support previously reported possible localizations (obtained from a separate collection of patients) of BP-I-susceptibility genes at two distinct sites on this chromosome. Current limitations of LD screening for identifying loci for complex traits are discussed, and recommendations are made for future research with these methods.

Linkage-disequilibrium mapping of disease genes by reconstruction of ancestral haplotypes in founder populations.

Linkage disequilibrium (LD) mapping may be a powerful means for genome screening to identify susceptibility loci for common diseases. A new statistical approach for detection of LD around a disease gene is presented here. This method compares the distribution of haplotypes in affected individuals versus that expected for individuals descended from a common ancestor who carried a mutation of the disease gene. Simulations demonstrate that this method, which we term "ancestral haplotype reconstruction" (AHR), should be powerful for genome screening of phenotypes characterized by a high degree of etiologic heterogeneity, even with currently available marker maps. AHR is best suited to application in isolated populations where affected individuals are relatively recently descended (< approximately 25 generations) from a common disease mutation-bearing founder.

Absolute pitch: an approach for identification of genetic and nongenetic components.

Absolute pitch (AP) is the ability to recognize a pitch, without an external reference. By surveying more than 600 musicians in music conservatories, training programs, and orchestras, we have attempted to dissect the influences of early musical training and genetics on the development of this ability. Early musical training appears to be necessary but not sufficient for the development of AP. Forty percent of musicians who had begun training at <=4 years of age reported AP, whereas only 3% of those who had initiated training at >=9 years of age did so. Self-reported AP possessors were four times more likely to report another AP possessor in their families than were non-AP possessors. These data suggest that both early musical training and genetic predisposition are needed for the development of AP. We developed a simple computer-based acoustical test that has allowed us to subdivide AP possessors into distinct groups, on the basis of their performance. Investigation of individuals who performed extremely well on this test has already led us to identify several families that will be suitable for studies of the genetic basis of AP.

A complete genome screen for genes predisposing to severe bipolar disorder in two Costa Rican pedigrees.

Bipolar mood disorder (BP) is a debilitating syndrome characterized by episodes of mania and depression. We designed a multistage study to detect all major loci predisposing to severe BP (termed BP-I) in two pedigrees drawn from the Central Valley of Costa Rica, where the population is largely descended from a few founders in the 16th-18th centuries. We considered only individuals with BP-I as affected and screened the genome for linkage with 473 microsatellite markers. We used a model for linkage analysis that incorporated a high phenocopy rate and a conservative estimate of penetrance. Our goal in this study was not to establish definitive linkage but rather to detect all regions possibly harboring major genes for BP-I in these pedigrees. To facilitate this aim, we evaluated the degree to which markers that were informative in our data set provided coverage of each genome region; we estimate that at least 94% of the genome has been covered, at a predesignated threshold determined through prior linkage simulation analyses. We report here the results of our genome screen for BP-I loci and indicate several regions that merit further study, including segments in 18q, 18p, and 11p, in which suggestive lod scores were observed for two or more contiguous markers. Isolated lod scores that exceeded our thresholds in one or both families also occurred on chromosomes 1, 2, 3, 4, 5, 7, 13, 15, 16, and 17. Interesting regions highlighted in this genome screen will be followed up using linkage disequilibrium (LD) methods.

Genetic mapping using haplotype, association and linkage methods suggests a locus for severe bipolar disorder (BPI) at 18q22-q23.

Manic depressive illness, or bipolar disorder (BP), is characterized by episodes of elevated mood (mania) and depression. We designed a multistage study in the genetically isolated population of the Central Valley of Costa Rica to identify genes that promote susceptibility to severe BP (termed BPI), and screened the genome ot two Costa Rican BPI pedigrees (McInnes et al., submitted). We considered only individuals who fulfilled very stringent diagnostic criteria for BPI to be affected. The strongest evidence for a BPI locus was observed in 18q22-q23. We tested 16 additional markers in this region and seven yielded peak lod scores over 1.0. These suggestive lod scores were obtained over a far greater chromosomal length (about 40 cM) than in any other genome region. This localization is supported by marker haplotypes shared by 23 of 26 BPI affected individuals studied. Additionally, marker allele frequencies over portions of this region are significantly different in the patient sample from those of the general Costa Rican population. Finally, we performed an analysis which made use of both the evidence for linkage and for association in 18q23, and we observed significant lod scores for two markers in this region.

HIV transmission in sexual networks: an empirical analysis.

Risk behaviour and egocentric sexual network data collected from a large random sample of young gay men in San Francisco were analysed to assess the importance of sexual mixing (i.e. sexual networks) in the acquisition of HIV. These data were collected in 1993, during wave one of a longitudinal cohort study of HIV transmission in gay men; the seroprevalence level in the sample was 18%. We identify recent sexual mixing patterns and we demonstrate that seropositives and seronegatives have very different age-stratified sexual mixing patterns. We show that sexual mixing can explain the current seroprevalence patterns in the young gay community; seroprevalence levels in risk groups reflect the degree of sexual mixing with the older (and more heavily infected) age group. Our results suggest that seropositives became infected with HIV not simply owing to an increased rate of acquisition of sex partners, but also as a result of their sexual mixing pattern. We develop and apply a simple methodology that uses the sexual network data in combination with risk behaviour data to estimate the future number of seroconverters. Our methodology is validated by testing our predictions against the observed seroconversion data collected during wave two of the cohort study in 1994. Our analyses empirically demonstrate (for the first time) the significance of sexual mixing as a risk factor for HIV transmission.