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However, now that large-scale outbred populations have failed in explaining the heritability of most complex diseases, and studies are more focused on the role of rare variation which could have larger effect sizes, there is renewed interest in performing studies in genetic isolates [ 71 ].
Genetically isolated populations are a powerful resource for the discovery of loci which may be common in the isolate, but rare and difficult to capture in outbred populations [ 71 ]. The unique genetic, social, and environmental characteristics of isolated populations can be used to expedite the discovery of disease-associated loci. Isolated populations are formed when a subpopulation is derived from a small number of founders as a result of events such as famine, war, infectious disease epidemics, settlement in a new territory, social and cultural barriers, environmental disruption, etc.
The resulting geographical or cultural isolation has important consequences. Decreased gene flow from neighboring populations and increased endogamy in population isolates often result in increased genomic homogeneity. Population isolates also tend to have environmental and cultural homogeneity [ 72 - 73 ]. Thus, the individuals tend to share a common lifestyle, and have similar exposure to environmental factors.
Many isolates also experience multiple population bottlenecks a marked reduction in sample size followed by survival and expansion of a small random sample of the original population which alternates with periods of rapid growth, resulting in independent branching and formation of regional subisolates [ 72 ]. For instance, in Finland both younger and older population isolates have appeared within one geographical region [ 72 ]. As an isolate recovers from the bottleneck, mating occurs between individuals who share a common ancestor.
This reduces genetic variability, and affects allele frequencies in the isolated population. Another important aspect of population isolates is that they tend to have very different demographical histories which are influenced by a number of factors such as the total number of founders, number and intensity of bottlenecks, and age and duration of isolation [ 73 ]. Detailed genealogical records are frequently available for isolated populations. Isolation and population bottlenecks result in genetic drift random fluctuations in allele frequencies as genes are transmitted from one generation to another which influences the genetic make-up of a population isolate.
Both disease-associated alleles and neutral alleles are subjected to genetic drift in a population isolate [ 72 ].
As a result, some disease alleles are lost, whereas others become enriched. Consequently, every population isolate has specific recessive diseases, which are expressed at a higher prevalence in one isolate, but which may be near absent in others [ 74 ].
Certain alleles reach fixation or extinction at a particular locus, which is due to genetic drift. Similarly, diseases causing variants which were rare in the founder population can drift to a much higher frequency in the subsequent generation [ 72 ]. This reduced genetic variability and higher frequency of disease-associated alleles can help in the identification of these variants with smaller sample sizes in isolated populations. Isolation and subsequent genetic drift also affect the haplotype complexity [ 73 ]. HapMap and genome projects have significantly contributed to the understanding of linkage disequilibrium in outbred populations.
In contrast to outbred populations, studies of isolated populations have identified extended genomic regions of linkage disequilibrium [ 77 - 78 ]. As expected, older population isolates tend to have shorter regions of linkage disequilibrium than younger population isolates. However, relatively extended regions of linkage disequilibrium can be observed in population isolates with a small number of founder individuals; this may result in a slower rate of growth following a bottleneck [ 79 ].
Genetic drift affects rare markers and rare haplotypes in the same way as it affects rare disease alleles. Some rare marker haplotypes can drift up in frequency while others are completely lost. Common marker haplotypes are rarely lost unless the number of founder individuals is very small [ 72 ]. Isolation, population bottlenecks, and consanguinity lead to a more uniform genetic background. Population isolates have extended regions of linkage disequilibrium and longer haplotypes, requiring fewer markers for GWASs and empowering imputation approaches that depend on predicting haplotype structure.
As rare variants are more recent in origin, they are more likely to be geographically localized. It is also possible that these variants may drift up in frequency in geographically isolated, high-risk populations, which makes the detection of such variants easier.
Alternatively, rare alleles could drift down and reach extinction, reducing the extent of genetic variability. Variability within a sample of individuals can be a consequence of environmental and lifestyle influences, and can also lead to differences in the genetic predisposition to T2D. For example, it has been shown that the T2D-predisposing alleles have a higher genetic effect in lean cases than in obese cases [ 80 ].
Also, for 36 known T2D-associated variants analyzed in this study, 29 had a higher OR for T2D in lean cases, and the overall weighted per-risk allele OR was higher in lean cases than in obese cases [ 80 ]. This finding was confirmed in a study of 13, American Indians who exhibited a significant SNP genotype x BMI interaction, such that the effect of the T2D risk allele was stronger in leaner individuals [ 81 ].
Genetic drift following a population bottleneck results in the enrichment of certain diseases which may have been rare in the original population. As disease prevalence affects statistical power for genetic association studies, it follows that fewer subjects are required to study a disease with a high population-based frequency, as compared to a low-frequency disease. Variability in association studies may be due to differences in phenotype definition.
Smaller population size allows for standardized assessment and characterization of phenotypes, leading to limited variability. Many isolates have good genealogical records due to less migration and more intact families. This provides opportunities for studying a cohort longitudinally, recalling subjects based on genotype, obtaining health records, and conducting family-based association studies.
Research groups have studied the heritability of T2D in different isolated populations, and have provided valuable insights into the genetic pathophysiology of T2D. Below are listed some of the isolated populations in whom genetic studies of T2D have resulted in increased understanding of the disease. The ancestors of American Indians who now live in the Gila River Indian Community in Arizona were the first people to arrive in the Americas 30, years ago. They have continued to live in the Sonoran desert near the Gila River in Southern Arizona for more than 2, years.
Exploring Spaniards called them Pima Indians. Archaeological finds suggest that the modern day Pima Indians descended from the Hohokam, "those who have gone", prehistoric people who originated in Mexico. Migrating from Mexico, they settled in the land up to where the Gila River and the Salt River meet, in what is now Arizona [ 82 - 83 ]. Modern day Pima Indians living in Arizona have minimal European admixture [ 84 ].
The Pima Indians were master weavers and farmers, and established a sophisticated system of irrigation to help with the farming needs [ 85 ]. Subsequent settlement of the west by people of European ancestry led to the disruption of the irrigation system, effecting Pima agriculture. This resulted in curtailment of subsistence farming, and led to fundamental changes in the lifestyle of Pima Indians from the Gila River. Most of the people from the tribe became dependent on government-issued foods. Early description of Pima Indians from the 's suggested that diabetes was either rare or not diagnosed at that time [ 86 - 87 ].
In late 's, Joslin identified 21 Pima Individuals with diabetes by reviewing medical records from hospitals serving the Pima population [ 88 ]. A survey of rheumatoid arthritis among Pimas in conducted by the National Institutes of Health led to the discovery of an extremely high rate of diabetes among Pima Indians. Two years later, the National Institutes of Health, the Indian Health Service, and the Pima community started a cooperative effort to understand the etiology of this disease.
From to , a systematic longitudinal study of Pima Indians from the Gila River Community was performed, focused on diabetes research. Individuals, predominantly Pima or the closely related Tohono O'Odham, greater than 5 years of age, were invited to participate in a biennial health examination that included a 75 g oral glucose tolerance test OGTT for assessing diabetes status, measurement of BMI, information on pregnancy and health of children, and assessment of diabetes-related complications [ 9 ].
Genealogical information was also documented. This longitudinal study identified an extremely high rate of T2D in Pima Indians. Although the precise reasons underlying the high prevalence and incidence of T2D is not known, genetic factors and higher rates of obesity due to life style changes are suspected as major culprits [ 9 , 89 ].
This rapid rise in T2D prevalence in Pima Indians living in Arizona has been followed by a relatively stable incidence rate [ 91 ]. However, the onset of diabetes has shifted to a younger age. During the past years, the incidence of diabetes among Pima Indians less than 15 years of age has increased nearly six-fold.
This shift to a younger age of onset may be a consequence of increasing rates of obesity in children and young adults [ 92 ]. Despite diabetes being diagnosed in Pima children as young as 3 years of age, diabetes in this American Indian tribe is exclusively T2D. Diabetes in Pima Indians lacks characteristics of type 1 diabetes such as insulin dependence, low levels of islet cells, and glutamic acid decarboxylase antibodies [ 93 - 94 ]. The absence of type 1 diabetes, a relatively younger onset of diabetes, and minimal admixture with European populations may indicate a more homogenous background for the disease.
Additionally, the relatively young age of onset of diabetes in Pima Indians allows for a better estimate of "affected" vs. These examinations included assessing the determinants of T2D when the individual was non-diabetic. Physiologic tests included a 75 g OGTT with measures of insulin at fasting, 30, 60, and minutes.
Body composition was measured by underwater weighing and later by dual X-ray absorptiometry. Acute insulin release was measured in response to a 25 g intravenous bolus of glucose and insulin action determined by a euglycemic-hyperinsulinemic clamp [ 1 ]. DNA for genetic analysis was obtained from participants of the longitudinal study and the inpatient study. Earliest immigrants settled in Pennsylvania, whereas latter groups settled in other Midwestern states.
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Approximately families settled in Lancaster County and are considered founders of the current Lancaster Amish Community. As of the year , the Amish population in and around Lancaster has exceeded 30, In , the Amish Family Diabetes Study was initiated in Lancaster to identify genetic determinants of T2D and related traits [ 95 - 97 ]. The Amish represent a religious isolate. Members of this faith are conservative Christians whose rural lives are guided by Ordnung, which promotes religious devotion and family and community cohesion.
The primary livelihood is farming, although modern agricultural machinery is not allowed. Use of other technology such as automobiles is also not allowed. The influence of the surrounding culture is minimal. Marriages from outside the sect are not allowed and individuals rarely immigrate [ 98 ].
Marriages between first cousins are not allowed, but on average, married couples are more closely related than second cousins once removed, but less related than second cousins [ 99 ]. Family genealogies are well documented, dating back to s [ 95 ].
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The Old Order Amish also have extensive genealogical records which is useful in genetic studies. Although the Amish are very physically active because of their abstinence from modern technologies, Snitker et al. Higher BMI is a risk factor for the development of diabetes. However, a lower rate of conversion from impaired glucose tolerance to overt T2D in Amish suggest that physical activity may protect against T2D independent of weight loss [ ].
The vast majority of Finns descended from two immigration waves occurring 4, and 2, years ago [ 72 ]. The earlier were eastern Uralic speakers, and the later were Indo-European speakers from the south. Both Y chromosomal haplotype and mitochondrial sequencing confirm the low genetic diversity among Finns compared to other European populations. The size of the founding population is not known, but as late as the twelfth century, the population was estimated to be only 50, [ 72 ]. The population size reached , before the great famine of wiped out one third of the population.
Since then, the Finnish population has expanded to more than 5,, In the sixteenth century, during the reign of Swedish king Gustavus of Vasa , internal migrations created regional subisolates. This time period also saw the establishment of a national system of population records which served as an important resource for later genetic studies. Approximately 30 recessive diseases are highly enriched in Finland, whereas diseases like phenylketonuria and cystic fibrosis are almost nonexistent [ 72 ]. In the year , there were , people with diabetes in Finland.
This rapid increase in T2D was mostly due to unhealthy eating habits and reduced physical activity [ ]. The population of Iceland was founded in the ninth and tenth century by a limited number of settlers from Norway, Ireland, and Scotland [ 72 ]. The country has experienced little immigration over the past centuries, and most of the current residents are descendants of the early settlers. A tradition of keeping family trees provides a unique resource to track the heredity of many diseases over hundreds of years [ 72 ].
Greenland was believed to be settled by descendants of the present Inuit culture, who identify the island as Kalaalit Nunaat, "land of the people". But these early Inuit people disappeared from the land about 3, years ago for unknown reasons. These were followed by the "Dorset" and the "Thule". In the 18 th century, Europeans returned to Greenland, predominantly from Norway and Denmark, and in Denmark claimed the island as a colony. In , a popular referendum gave Greenland "home rule" status as a distinct nation within the kingdom of Denmark.
A hard-to-access geography along with the harsh climate may have made the settlement of the island difficult. The relative isolation from other regions and successive waves of migration may have created conditions for strong bottleneck and other effects of genetic drift. There is a certain amount of European influence in Greenland culture, but the island nonetheless features unique Inuit and European cultures that are distinct from one another. Indeed, they found that these features were much more dramatic than the "founder" populations of Finland and Iceland. Studies have also reported an increased prevalence of obesity and T2D in natives from Kosrae, similar to that seen in other indigenous populations [ ].
This Croatian island population is primarily of Slavic descent, originating from people who emigrated from the mainland at successive time periods [ - ]. This population has remained largely isolated mainly because of geographic separation with minimal immigration from the mainland. Although they share a common descent with Europeans, they are different culturally, practicing a traditional life style based on agricultural subsistence in a rural setting and living on a typical "Mediterranean diet" [ ].
However, studies have shown an increased prevalence of obesity and hypertension in this population, suggesting factors other than lifestyle contributing to these conditions [ ]. The Oji-Cree is a native Canadian population residing in a narrow band extending from the Missinabi river region in Northeastern Ontario at the east and Lake Winnipeg at the west. The Oji-Cree people are descended from historical intermarriage between the Ojibwa and Cree cultures, but are considered a distinct nation from either parent groups.
Consequently, this population has been studied to understand the genetic factors responsible for this disease [ ]. Studies in isolated populations to delineate the heritability of T2D followed much the same pattern as studies in outbred populations. Initial work focused on candidate gene association studies, family-based linkage studies, and GWASs. Recent studies have also utilized whole genome or whole exome sequence data to identify potentially functional variants that were not captured in commercially available genotyping arrays.
Some studies in isolated populations have led to several important observations which are either highly significant for the studied population or have advanced our understanding of the pathophysiology of diabetes. Several examples are detailed below. In , Hegele et al. Among the subgroups examined, the association was strongest in adolescent individuals [ ].
Even though Oji-Cree subjects without this variant display characteristic features of T2D that include obesity, high plasma insulin levels, and insulin resistance, the diabetic phenotype of GS carriers is more consistent with a defect in insulin secretion, with an earlier onset of diabetes, less obesity, and lower insulin levels, as compared to non-carriers [ ]. The mutation was identified using a focused candidate gene approach which analyzed genes that code for proteins known to play a role in diabetes pathophysiology and genes in which mutations were reported to cause MODY reviewed in [ ].
Therefore, this gene was studied for sequence variation, leading to the discovery of the GlySer mutation which associated with T2D. To date, the GlySer mutation has not been detected in other ethnic groups. HNF1A belongs to the homeobox gene family of transcription factors and is expressed in the pancreas. It acts as a transcription activator for many genes including insulin [ ]. In-vitro functional studies have shown that the GS mutation does not affect DNA binding or dimerization of HNF1A, but significantly reduces its capacity to transactivate gene expression. This difference in functional impact may explain a reduced penetrance seen with the GS mutation resulting in T2D [ ].
Recent functional studies have also shown that the GS variant produces two abnormal transcripts that alter the relative ratio of normal splicing products. This combination of abnormal splicing and reduced activity of the GS protein are the underlying cause of the increase in diabetes susceptibility associated with this mutation [ ].
Variations associated with T2D in other genes have also been reported in Oji-Cree. Lipolysis plays an important role in energy homeostasis. A study in the Old Order Amish analyzed sequence data from 12 lipolytic-pathway genes in subjects whose fasting triglyceride levels were at the extremes of the distribution, and identified a bp frameshift deletion in exon 9 of LIPE , a key enzyme for lipolysis [ ]. LIPE encodes hormone-sensitive lipase HSL , and primarily hydrolyzes stored triglycerides to free fatty acids in adipose tissue and heart, whereas in steroidogenic tissues, it converts cholesteryl esters to free cholesterol for steroid hormone production.
All four subjects who were homozygous for the deletion were diagnosed with T2D before the age of 50 years [ ]. Analysis of adipose tissue from study participants who were homozygous for the deletion suggests that the mutation results in the complete absence of HSL protein and a downregulation of transcription factors responsive to PPARG and downstream target genes. Small adipocytes, impaired lipolysis, insulin resistance, and inflammation were also noted [ ].
These studies highlight the importance of lipolysis in systemic lipid and glucose homeostasis, and the important role of HSL in this process [ ]. In a community-based study of Pima Indians, 3. Among the 7, individuals genotyped, only one individual was homozygous for this mutation. The clinical course of this individual included hypoglycemia, with seizures at the age of 4 months due to hyperinsulinemia, and a diagnosis of diabetes at 3. The RH also associated with birth weight where newborns who carried this mutation were approximately grams heavier than non-carriers [ ].
This is consistent with the hypothesis of fetal hyperinsulinemia, resulting in increased birth weight. The mutation was functionally characterized, and in vitro studies showed that it reduced KATP channel activity [ ]. Other groups have reported that individuals with congenital hyperinsulinemia due to inactivating ABCC8 mutations eventually developed early- and adult-onset diabetes [ , ]. Identification of a loss-of-function variant in ABCC8 with a carrier frequency of 3. This may have an impact on clinical practice since homozygous carriers may develop hyperinsulinemic hyperglycemia in infancy [ ].
Functional studies implicate that DNER regulates notch signaling pathway genes in pancreatic beta-cells [ 47 ]. It has previously been shown that rare mutations in GCK encodes glucokinase can cause MODY as a consequence of reduced glucose-stimulated insulin secretion. Glucokinase is the main glucose-phosphorylating enzyme in liver and pancreatic beta-cells, where it converts glucose to G6P as a first and rate-limiting step in glycolysis.
In a study of Pima Indians, a novel variant in the 3'UTR of GCK was associated with a lower rate of carbohydrate oxidation, lower hr energy expenditure, and higher risk of T2D [ ]. The finding of a lower rate of glucose oxidation, observed post-absorptively, during insulin stimulation, and after a diet of mixed consumption, is consistent with a role of GCK in glycolysis. This variant was not associated with non-oxidative glucose disposal, suggesting that glucose storage glycogen synthesis was not affected [ ].
Large-scale array-based genotyping and exome sequencing in individuals from Greenland led to the identification of a common nonsense mutation p. This further highlights the importance of studying diverse populations. As detailed above, identification of disease alleles for complex diseases may be simplified by studies in isolated populations because of increased genomic, environmental, and cultural homogeneity [ 72 , 73 ].
However, this advantage must be balanced with the fact that much of the currently available technology has been customized from outbred populations. For example, commercially available SNP arrays were primarily designed using haplotype and sequence information from outbred populations. Consequently, the SNPs included in these arrays may be less informative for isolated populations because of the difference in linkage disequilibrium and failure to capture variants that are either novel to a population or that occur at a much higher frequency than in outbred populations.
Therefore, in addition to performing GWASs, many studies in isolated populations have directly assessed risk alleles identified in outbred populations to determine their effect in isolated populations. These variants were further associated with diabetes-related traits, including adiposity rs , 2-hr glucose, and insulin resistance rs [ ].
Importantly, this study identified an independent variant at the LPP locus which was not reported in the trans-ancestry analysis, highlighting the importance of studying a diverse population for genetics of complex traits [ ]. Recently, Hanson et al. Eight of these variants were nearly monomorphic in Pima Indians, and nine SNPs showed significant heterogeneity in effect between Pima Indians and Europeans, which may be explained by different patterns of linkage disequilibrium [ ].
A relatively smaller sample size available for the study of isolated populations may be one of the reasons that T2D-associated variants identified in outbred populations do not achieve statistical significance in isolated populations. However, a genetic risk score derived from all established loci was strongly associated with T2D and with lower insulin secretion in Pima Indians [ ]. In a similar study of the role of established T2D and BMI loci on metabolic traits measured in an island population from Croatia, a significant association of TCF7L2 variants with fasting plasma glucose and HbA1c levels was reported [ ].
Several studies have investigated whether the difference in the prevalence of T2D among different populations is attributable to population differences in the frequencies of T2D risk alleles [ , ]. Recent reports suggest that the difference in allele frequency at established T2D loci between major continental populations is greater than expected, given the genetic distance between the major continental populations.
A gradient in genetic risk for T2D has also been proposed, with risk alleles having highest frequencies in Africans and those of lowest frequencies in East Asians [ , , ]. Such divergence in allele frequency at disease-associated loci may represent an effect of natural selection along the course of the evolutionary history of these populations [ ]. Given the very high prevalence of T2D in Pima Indians, one might expect higher frequencies of established T2D risk alleles in this isolated population. A recent study by Hanson et al. The authors formally tested the significance of the difference in risk allele frequency between Pimas and other major HapMap populations [ ].
A mean genetic risk score was used to determine whether T2D risk alleles were systematically higher in one population than another. The genetic distances calculated as fixation index F ST across the T2D loci between Pimas and other continental populations were not significantly different than distances derived using randomly selected markers. This observation suggests that the difference in allele frequency at T2D loci between Pima Indians and other populations is not as different as expected, despite the large genetic distance [ ].
The genetic attributable fraction was also calculated; it is defined as the proportion of excess T2D prevalence in a "high-risk population" in relation to a "reference population" that is due to difference in risk allele frequency. In the left panel A , the GRS was calculated as the sum of the number of risk alleles across 63 type 2 diabetes loci, while in the right panel B it is the sum of the number of risk alleles multiplied by log OR , as determined in Europeans.
Modified from [ ]. The age-sex-adjusted prevalence of T2D was significantly higher in Pima Indians than in non-Hispanic whites When adjusted for the frequency of the risk allele in non-Hispanic whites Pima adjusted , the prevalence in Pimas was slightly higher The "adjusted" value represents the age-sex-adjusted prevalence for the target population adjusted to the frequency of the risk alleles in the reference population across all 63 loci.
Genomic imprinting is a mechanism by which certain genes are expressed in a parent-of-origin-specific manner. If the paternally-derived allele is imprinted, then it is silenced, and the gene is expressed only from the maternally-derived allele and vice versa.
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Some of the genetic loci associated with T2D map to regions of the genome that are imprinted. However, knowledge of the parental genotypes is required to determine whether variants in imprinted regions have a parent-of-origin effect on disease risk. An Icelandic study was the first to report a parent-of-origin effect for several loci using a combination of genealogy and long-range phasing to determine the parental origin of alleles [ 62 ].
A second variant in KCNQ1 , rs, which is not substantially correlated with rs, also showed a maternal inheritance effect on T2D [ 62 ].
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Similar results were seen for rs at the KLF14 locus where the effect was again restricted to maternally inherited allele [ 62 ]. The strongest effect was seen at the KCNQ1 locus. This represents one of the largest single SNP contributions to T2D risk reported in any population, and demonstrates the importance of collecting family-based data and DNA, which is often facilitated by studying isolated populations where family members have not dispersed.
Although efforts in the past decade have greatly advanced our understanding of DNA variation contributing to T2D, this knowledge currently has very limited predictive and translational value. Most of the loci identified to date have no known established function in the pathophysiology of T2D; they have been designated as "T2D loci" solely based on their proximity to a GWAS signal. A clear demonstration of causality at the gene and variant level will be important to increase the usefulness of these results in both basic science and translational studies.
Whole genome sequencing studies using next generation sequencing, which are currently being explored, may help to achieve these aims. As genomic studies move farther and farther away from hypothesis-based efforts, and instead aim to explore all genomic information, the complexity of T2D can be daunting. As suggested in a recent review by Froguel et al. National Center for Biotechnology Information , U. Journal List Rev Diabet Stud v. Published online Nov Nair and Leslie J. This article has been cited by other articles in PMC. Abstract Genetic studies in large outbred populations have documented a complex, highly polygenic basis for type 2 diabetes T2D.
Type 2 diabetes - an introduction Diabetes is a metabolic condition defined by elevated serum glucose levels. Type 2 diabetes is heritable Several lines of evidence, as detailed below, have documented a genetic basis for T2D. Delineating the heritability of T2D Identifying genetic factors that influence the pathophysiology of T2D has proved to be challenging. Open in a separate window. Loci that harbor variants associated with type 2 diabetes [10, 47, 68, 87, , , , ] Red circle: What have we learned about the heritability of T2D?
However, based on GWAS data where common variants do not explain the high prevalence of the disease, other mechanisms have been proposed that include: The broad sense heritability model: The following aspects are to be considered with this procedure: Specific risk alleles might occur in specific populations only e. MYBPC3 locus for cardiomyopathy [ 61 ]. The differences in recombination, mutation, and divergence of genealogical lineages can influence how easily one variant can be detectable in one population compared to other. Disease prevalence may vary among populations, which may affect power, making detection in some populations more likely than in others.
The risk variants can have different effect sizes in different populations e.
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Using isolated populations to study complex diseases Family-based association studies in population isolates have been successful in identifying loci associated with Mendelian traits [ 70 ]. Advantages of studying population isolates for complex diseases 6. Population Isolates studied for T2D Research groups have studied the heritability of T2D in different isolated populations, and have provided valuable insights into the genetic pathophysiology of T2D. Results of studies of T2D in isolated populations Studies in isolated populations to delineate the heritability of T2D followed much the same pattern as studies in outbred populations.
Comparison of T2D loci in isolated vs.
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Exploring an additional heritable mechanism: Going forward Although efforts in the past decade have greatly advanced our understanding of DNA variation contributing to T2D, this knowledge currently has very limited predictive and translational value. Don't know who the maker is but included a photo of the impressed Mark. The cup and Saucer are attractive in design and stamped Alvingham on the base. The cup and Saucer are in good condition and is as pictured.
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