Contribution of consanguinuity to polygenic and multifactorial diseases

Rudan, Igor; Campbell, Harry; Carothers, Andrew D.; Hastie, Nicholas D.; Wright, Alan F.

doi:10.1038/ng1106-1224

Cited by 44 publications

(37 citation statements)

References 8 publications

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“…The genetic determination of uric acid seems to fit well into the polygenic trait theory, where a number of genes are expected to influence a single trait (55). However, uric acid also seems to be under strong single gene effect of SL-C2A9, which was described to explain up to 5% of variance of uric acid in women (10).…”

Section: Discussionmentioning

confidence: 95%

Predictive Value of 8 Genetic Loci for Serum Uric Acid Concentration

et al. 2010

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AimTo investigate the value of genomic information in prediction of individual serum uric acid concentrations.Methods Three population samples were investigated: from isolated Adriatic island communities of Vis (n = 980) and Korčula (n = 944), and from general population of the city of Split (n = 507). Serum uric acid concentration was correlated with the genetic risk score based on 8 previously described genes: PDZK1, GCKR, SLC2A9, ABCG2, LR-RC16A, SLC17A1, SLC16A9, and SLC22A12, represented by a total of 16 single-nucleotide polymorphisms (SNP). The data were analyzed using classification and regression tree (CART) and general linear modeling. ResultsThe most important variables for uric acid prediction with CART were genetic risk score in men and age in women. The percent of variance for any single SNP in predicting serum uric acid concentration varied from 0.0%-2.0%. The use of genetic risk score explained 0.1%-2.5% of uric acid variance in men and 3.9%-4.9% in women. The highest percent of variance was obtained when age, sex, and genetic risk score were used as predictors, with a total of 30.9% of variance in pooled analysis. ConclusionDespite overall low percent of explained variance, uric acid seems to be among the most predictive human quantitative traits based on the currently available SNP information. The use of genetic risk scores is a valuable approach in genetic epidemiology and increases the predictability of human quantitative traits based on genomic information compared with single SNP approach. Uric acid is the end product of purine metabolism in humans and higher primates and was initially believed to be a highly potent risk factor for disease development (1). This was confirmed in different studies that reported increased levels of serum uric acid in metabolic disorders and cancer (2-4). However, recent studies have reported possible beneficial effects of uric acid, especially in cardiovascular and neurological diseases of late onset (5,6). Possible protective effects are due to a strong antioxidant properties of uric acid (7). All these findings make uric acid a highly interesting research target in both epidemiology and genetics.Efforts in the search for the genetic basis of uric acid concentrations have been focused on several candidate genes (8,9) and the recently described SLC2A9 has been found to be a gene with a major effect in humans, especially in women (10,11). SLC2A9, also known as Glut 9, is a member of the SLC2A facilitative glucose transporter family, which has an important role in the sugars metabolism (12). The gene encodes a putative transporter of 540 amino acids, which is closely related to several more members of the same gene family, with 44% and 38% resemblance to Glut5 and Glut1, respectively (12). The protein consists of 12 transmembrane domains, sugar motifs, and other signatures which facilitate sugars transport (13). The long form of this protein in humans is most strongly expressed in basolateral membranes of proximal renal tubular cells, the liver, and placenta, w...

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Section: Discussionmentioning

confidence: 95%

Predictive Value of 8 Genetic Loci for Serum Uric Acid Concentration

et al. 2010

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“…A limited number of reports have focused on the inbreeding effect on multifactorial disorders (Jaber et al 1997;Soliman et al 1999;Bener et al 2001;Rudan et al 2003Rudan et al , 2006Hamamy et al 2005;Alzolibani 2009;Mansour et al 2009). These studies have revealed an important role of inbreeding in the etiology of many specific diseases following a multifactorial pattern of inheritance like diabetes mellitus, hypertension, mental disorders, and cancer.…”

Section: Introductionmentioning

confidence: 99%

Consanguinity, endogamy, and genetic disorders in Tunisia

et al. 2012

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“…16 Third, we applied this approach to investigate the effects of h on a range of biomedically relevant human quantitative traits with two main conclusions: (i) our estimated h-values showed a very high correlation with genealogical expectations; and (ii) we showed statistically significant associations between h and blood pressure and cholesterol levels. 17 To further investigate our general hypothesis that global outbreeding could have substantial effects on burden of disease, 11 we need to quantify the typical increase in average h that occurs during isolate break-up and urbanisation, which we attempted to do in this study.…”

Section: Introductionmentioning

confidence: 99%

“…8 -10 Furthermore, increased heterozygosity at the individual level could in theory improve resistance to detrimental factors in the environment, especially infectious diseases, and could delay the onset of many chronic diseases. 11,12 Finally, outbreeding should decrease the burden of recessive monogenic conditions that are characteristic of large global communities with a high prevalence of consanguineous marriages. 13,14 Because of these potential effects of h on health we considered it important to quantify the magnitude of increase in h that is associated with urbanisation relative to traditional rural populations.…”

Section: Introductionmentioning

confidence: 99%

Quantifying the increase in average human heterozygosity due to urbanisation

et al. 2008

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The human population is undergoing a major transition from a historical metapopulation structure of relatively isolated small communities to an outbred structure. This process is predicted to increase average individual genome-wide heterozygosity (h) and could have effects on health. We attempted to quantify this increase in mean h. We initially sampled 1001 examinees from a metapopulation of nine isolated villages on five Dalmatian islands (Croatia). Village populations had high levels of genetic differentiation, endogamy and consanguinity. We then selected 166 individuals with highly specific personal genetic histories to form six subsamples, which could be ranked a priori by their predicted level of outbreeding. The measure h was then estimated in the 166 examinees by genotyping 1184 STR/indel markers and using two different computation methods. Compared to the value of mean h in the least outbred sample, values of h in the remaining samples increased successively with predicted outbreeding by 0.023, 0.038, 0.058, 0.067 and 0.079 (Po0.0001), where these values are measured on the same scale as the inbreeding coefficient (but opposite sign). We have shown that urbanisation was associated with an average increase in h of up to 0.08-0.10 in this Croatian metapopulation, regardless of the method used. Similar levels of differentiation have been described in many populations. Therefore, changes in the level of heterozygosity across the genome of this magnitude may be common during isolate break-up in humans and could have significant health effects through the established genetic mechanism of hybrid vigour/heterosis.

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Contribution of consanguinuity to polygenic and multifactorial diseases

Cited by 44 publications

References 8 publications

Predictive Value of 8 Genetic Loci for Serum Uric Acid Concentration

Predictive Value of 8 Genetic Loci for Serum Uric Acid Concentration

Consanguinity, endogamy, and genetic disorders in Tunisia

Quantifying the increase in average human heterozygosity due to urbanisation

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