Association between SNP Heterozygosity and Quantitative Traits in the Framingham Heart Study

Govindaraju, Diddahally R.; Larson, Martin G.; Yin, Xiaoyan; Benjamin, Emelia J.; Rao, Marepalli B.; Vasan, Ramachandran S.

doi:10.1111/j.1469-1809.2009.00514.x

Cited by 17 publications

(14 citation statements)

References 52 publications

(54 reference statements)

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“…High levels of heterozygosity should correspond to lower risks of reinforcing rare deleterious variants, leading to protection from disease. Higher heterozygosity has been associated with lower blood pressure and cholesterol (Campbell et al 2007;Govindaraju et al 2009) and lower plasma cortisol (Zgaga et al 2013). However, a recent study failed to find any significant associations of a heterozygosity measure and a range of endophenotypes with coronary heart disease (Mukamal et al 2015).…”

mentioning

confidence: 97%

Heterozygosity Ratio, a Robust Global Genomic Measure of Autozygosity and Its Association with Height and Disease Risk

Samuels¹,

Wang²,

et al. 2016

Genetics

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Greater genetic variability in an individual is protective against recessive disease. However, existing quantifications of autozygosity, such as runs of homozygosity (ROH), have proved highly sensitive to genotyping density and have yielded inconclusive results about the relationship of diversity and disease risk. Using genotyping data from three data sets with .43,000 subjects, we demonstrated that an alternative approach to quantifying genetic variability, the heterozygosity ratio, is a robust measure of diversity and is positively associated with the nondisease trait height and several disease phenotypes in subjects of European ancestry. The heterozygosity ratio is the number of heterozygous sites in an individual divided by the number of nonreference homozygous sites and is strongly affected by the degree of genetic admixture of the population and varies across human populations. Unlike quantifications of ROH, the heterozygosity ratio is not sensitive to the density of genotyping performed. Our results establish the heterozygosity ratio as a powerful new statistic for exploring the patterns and phenotypic effects of different levels of genetic variation in populations.

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confidence: 97%

Heterozygosity Ratio, a Robust Global Genomic Measure of Autozygosity and Its Association with Height and Disease Risk

Samuels¹,

Wang²,

et al. 2016

Genetics

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“…(ii) Heterozygosity Individual multilocus observed heterozygosity (H o ) was determined as: where m is the number of loci successfully scored, and H ij is a binary variable that takes the value of 1 if the jth locus is heterozygous within the ith individual, and 0 otherwise [14]. We preferred multilocus observed heterozygosity (H o ) over other standardized measures of marker heterozygosity (e.g.…”

Section: (D) Fitness and Heterozygosity Estimates (I) Fitnessmentioning

confidence: 99%

“…amphibians [12]) or both (e.g. birds [13], humans [14] and plants; see [15] for a review). HFCs for specific loci rather than for genome-wide heterozygosity tend to predominate in the literature.…”

Section: Introductionmentioning

confidence: 99%

Local effects drive heterozygosity–fitness correlations in an outcrossing long-lived tree

et al. 2015

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Heterozygosity-fitness correlations (HFCs) have been used to understand the complex interactions between inbreeding, genetic diversity and evolution. Although frequently reported for decades, evidence for HFCs was often based on underpowered studies or inappropriate methods, and hence their underlying mechanisms are still under debate. Here, we used 6100 genome-wide single nucleotide polymorphisms (SNPs) to test for general and local effect HFCs in maritime pine (Pinus pinaster Ait.), an iconic Mediterranean forest tree. Survival was used as a fitness proxy, and HFCs were assessed at a four-site common garden under contrasting environmental conditions (total of 16 288 trees). We found no significant correlations between genome-wide heterozygosity and fitness at any location, despite variation in inbreeding explaining a substantial proportion of the total variance for survival. However, four SNPs (including two non-synonymous mutations) were involved in significant associations with survival, in particular in the common gardens with higher environmental stress, as shown by a novel heterozygosity-fitness association test at the species-wide level. Fitness effects of SNPs involved in significant HFCs were stable across maritime pine gene pools naturally growing in distinct environments. These results led us to dismiss the general effect hypothesis and suggested a significant role of heterozygosity in specific candidate genes for increasing fitness in maritime pine. Our study highlights the importance of considering the species evolutionary and demographic history and different spatial scales and testing environments when assessing and interpreting HFCs.

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“…The advantages of increased locus and multi-locus heterozygosity (MLH) for disease resistance, longevity and fitness, especially when the organism is challenged, have been described for several species including humans (8,9,10). However, the underlying mechanism for this 'heterozygosity-fitness correlation' is not clear, and the reported associations with infectious disease susceptibility and common complex disease risk factors are usually weak, perhaps due to the fact that most human populations are outbred with nearly uniform and high heterozygosity of individuals (11,12,13,14).…”

Section: Introductionmentioning

confidence: 99%

Individual multi-locus heterozygosity is associated with lower morning plasma cortisol concentrations

Zgaga

Vitart

Hayward

et al. 2013

European Journal of Endocrinology

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Objective: Stress is implicated as a risk factor for numerous illnesses in humans, putatively in part mediated by biological responses to stress, such as elevated cortisol concentrations. The theory of genetic homoeostasis suggests that individual heterozygosity facilitates compensation for environmental stresses. We hypothesized that heterozygosity ameliorates the biological response to a given level of perceived stress, reflected in lower plasma cortisol concentrations. Design: We examined the role of heterozygosity in the association between perceived psychological stress and morning cortisol concentrations in 854 individuals from the isolated island of Vis, Croatia. Methods: Cortisol concentrations were measured in morning plasma samples. A total of 1184 autosomal microsatellite markers were genotyped and individual multi-locus heterozygosity (MLH) was calculated as the proportion of heterozygous markers. The General Health Questionnaire with 30 items (GHQ-30) was used to assess the degree of psychological distress. Results: Mean MLH was 34.85G0.45% (range: 31.97-36.22%). Psychological distress (GHQ Likert score O31) was more prevalent in women (37 vs 18% in men, P!0.0001), in less educated people (bZK0.35 per year in school, P!0.001) and in lower socio-economic classes (bZK3.59, P!0.0001). Cortisol concentrations were positively associated with psychological distress (bZ2.20, PZ0.01). In a regression model adjusted for age, BMI, education and GHQ-30 score, MLH was independently and inversely associated with morning plasma cortisol concentrations (PZ0.005). Conclusion: More heterozygous individuals, as measured by microsatellite markers, had lower morning plasma cortisol concentrations for a given level of perceived psychological stress. This may be important, as higher cortisol concentrations may increase the allostatic load and be associated with a higher risk of stress-related illness.

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Association between SNP Heterozygosity and Quantitative Traits in the Framingham Heart Study

Cited by 17 publications

References 52 publications

Heterozygosity Ratio, a Robust Global Genomic Measure of Autozygosity and Its Association with Height and Disease Risk

Heterozygosity Ratio, a Robust Global Genomic Measure of Autozygosity and Its Association with Height and Disease Risk

Local effects drive heterozygosity–fitness correlations in an outcrossing long-lived tree

Individual multi-locus heterozygosity is associated with lower morning plasma cortisol concentrations

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