A genome-wide linkage study of individuals with high scores on NEO personality traits.

The NEO-Five-Factor Inventory divides human personality traits into five dimensions: neuroticism, extraversion, openness, conscientiousness and agreeableness. In this study, we sought to identify regions harboring genes with large effects on the five NEO personality traits by performing genome-wide linkage analysis of individuals scoring in the extremes of these traits (>90th percentile). Affected-only linkage analysis was performed using an Illumina 6K linkage array in a family-based study, the Erasmus Rucphen Family study. We subsequently determined whether distinct, segregating haplotypes found with linkage analysis were associated with the trait of interest in the population. Finally, a dense single-nucleotide polymorphism genotyping array (Illumina 318K) was used to search for copy number variations (CNVs) in the associated regions. In the families with extreme phenotype scores, we found significant evidence of linkage for conscientiousness to 20p13 (rs1434789, log of odds (LOD)=5.86) and suggestive evidence of linkage (LOD >2.8) for neuroticism to 19q, 21q and 22q, extraversion to 1p, 1q, 9p and12q, openness to 12q and 19q, and agreeableness to 2p, 6q, 17q and 21q. Further analysis determined haplotypes in 21q22 for neuroticism (P-values = 0.009, 0.007), in 17q24 for agreeableness (marginal P-value = 0.018) and in 20p13 for conscientiousness (marginal P-values = 0.058, 0.038) segregating in families with large contributions to the LOD scores. No evidence for CNVs in any of the associated regions was found. Our findings imply that there may be genes with relatively large effects involved in personality traits, which may be identified with next-generation sequencing techniques.

Linkage analysis of adult height in a large pedigree from a Dutch genetically isolated population.

Despite extensive research of genetic determinants of human adult height, the genes identified up until now allow to predict only a small proportion of the trait's variance. To identify new genes we analyzed 2,486 genotyped and phenotyped individuals in a large pedigree including 23,612 members in 18 generations. The pedigree was derived from a young genetically isolated Dutch population, where genetic heterogeneity is expected to be low and linkage disequilibrium has been shown to be increased. Complex segregation analysis confirmed high heritability of adult height, and suggested mixed model of height inheritance in this population. The estimates of the model parameters obtained from complex segregation analysis were used in parametric linkage analysis, which highlighted three genome-wide significant and additionally at least four suggestive loci involved in height. Significant peaks were located at the chromosomal regions 1p32 (LOD score = 3.35), 2p16 (LOD score = 3.29) and 16q24 (LOD score = 3.94). For the latter region, a strong association signal (FDR q < 0.05) was obtained for 19 SNPs, 17 of them were located in the CDH13 (cadherin 13) gene of which one (rs1035569) explained 1.5% of the total height variance.

Inheritance of litter size at birth in farmed arctic foxes (Alopex lagopus, Canidae, Carnivora).

Natural populations of the arctic fox (Alopex lagopus, Canidae, Carnivora) differ drastically in their reproductive strategy. Coastal foxes, which depend on stable food resources, produce litters of moderate size. Inland foxes feed on small rodents, whose populations are characterized by cycling fluctuation. In the years with low food supply, inland fox populations have a very low rate of reproduction. In the years with high food supply, they undergo a population explosion. To gain insight into the genetic basis of the reproductive strategy of this species, we performed complex segregation analysis of the litter size in the extended pedigree of the farmed arctic foxes involving 20,665 interrelated animals. Complex segregation analysis was performed using a mixed model assuming that the trait was under control of a major gene and a large number of additive genetic and random factors. To check the significance of any major gene effect, we used Elston-Stewart transmission probability test. Our analysis demonstrated that the inheritance of this trait can be described within the frameworks of a major gene model with recessive control of low litter size. This model was also supported by the pattern of its familial segregation and by comparison of the distributions observed in the population and that expected under our model. We suggest that a system of balanced polymorphism for litter size in the farmed population might have been established in natural populations of arctic foxes as a result of adaptation to the drastic fluctuations in prey availability.

Inheritance of white head spotting in natural populations of South American water rat (Nectomys squamipes Rodentia: Sigmodontinae).

Specimens with white head spots are present at low frequency in the natural populations of South American water rat (Nectomys squamipes) and absent in the sibling species Nectomys rattus. We analyzed the pattern of inheritance of the phenotype using complex segregation analysis of pedigrees of a captive-bred population of N. squamipes. We found that the inheritance of the white head spot in this species can be described within the framework of the major gene recessive model with incomplete penetrance of genotypes.

Segregation analysis of Scheuermann disease in ninety families from Siberia.

Scheuermann disease [OMIM number 181440] is the most common cause of structural kyphosis in adolescence. Segregation analysis using a model with gender effects was applied to 90 pedigrees from Barnaul (West Siberia, Russia) ascertained through a proband with Scheuermann disease. The transmission probability model was used to detect major gene effect. A significant contribution of a major gene to the control of the pathology was established. Inheritance of the disease can be described within the framework of a dominant major gene diallele model. According to this model, Scheuermann disease should never occur in the absence of the mutant allele. All male carriers of the mutant allele develop the disease, while only a half of female carriers manifest it. We found a high frequency of idiopathic scoliosis in the families with Scheuermann disease (0.08 vs. 0.01-0.02 in general population). We also observed a succession of idiopathic scoliosis and Scheuermann disease in consecutive generations. The familial aggregation of these two spinal pathologies in the present sample may indicate a genetic unity of Scheuermann disease and idiopathic scoliosis.

Segregation analysis of idiopathic scoliosis: demonstration of a major gene effect.

Segregation analysis using a model with age and gender effects was applied to 101 pedigrees ascertained through a proband with idiopathic scoliosis. The transmission probability model was used to detect major gene effect. When we analyzed the pedigrees where affected status was assigned to persons with a Cobb's angle of more than 5 degrees we did not detect a significant major gene effect. However, when the affected status was assigned to persons with pronounced forms of disease only (a curve of at least 11 degrees) a significant contribution of a major causal gene could be established and inheritance could be described according to a dominant major gene diallele model, assuming incomplete sex and age dependent penetrance of genotypes. According to this model, the pronounced forms of idiopathic scoliosis should never occur in the absence of the mutant allele. This indicates that only the carriers of the mutant allele develop pronounced forms of the disease. At the same time, only a fraction of the carriers of the mutant gene should manifest the disease (30% of males and 50% of females).