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Analysis and application of European genetic substructure using 300 K SNP information.

Tian C, Plenge RM, Ransom M, Lee A, Villoslada P, Selmi C, Klareskog L, Pulver AE, Qi L, Gregersen PK, Seldin MF - PLoS Genet. (2008)

Bottom Line: A second PC further separated Italian, Spanish, and Greek individuals from those of Ashkenazi Jewish ancestry as well as distinguishing among northern European populations.In addition, two sets of European substructure ancestry informative markers (ESAIMs) were identified that provide substantial substructure information.The results provide further insight into European population genetic substructure and show that this information can be used for improving error rates in association testing of candidate genes and in replication studies of WGA scans.

View Article: PubMed Central - PubMed

Affiliation: Rowe Program in Human Genetics, University of California Davis, Davis, California, United States of America.

ABSTRACT
European population genetic substructure was examined in a diverse set of >1,000 individuals of European descent, each genotyped with >300 K SNPs. Both STRUCTURE and principal component analyses (PCA) showed the largest division/principal component (PC) differentiated northern from southern European ancestry. A second PC further separated Italian, Spanish, and Greek individuals from those of Ashkenazi Jewish ancestry as well as distinguishing among northern European populations. In separate analyses of northern European participants other substructure relationships were discerned showing a west to east gradient. Application of this substructure information was critical in examining a real dataset in whole genome association (WGA) analyses for rheumatoid arthritis in European Americans to reduce false positive signals. In addition, two sets of European substructure ancestry informative markers (ESAIMs) were identified that provide substantial substructure information. The results provide further insight into European population genetic substructure and show that this information can be used for improving error rates in association testing of candidate genes and in replication studies of WGA scans.

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Analysis of European Substructure in Northern European Individuals(A) The first two PCs are depicted for RA cases and NYCP controls.(B) Color codes show the Irish contribution to each individual with at least two GP country of origin information in the sample set shown in (A), e.g., the 2GP Irish individuals have 2GP Irish origin and 2GP unknown or USA origin; Not Irish includes only individuals without known Irish ancestry and with at least 2GP information; mixed Irish are those individuals with at least one GP Irish and one GP non-Irish.(C) Analysis using 1,211 ESAIMs selected for differences along PC1 in northern European individuals (see Results).
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pgen-0040004-g004: Analysis of European Substructure in Northern European Individuals(A) The first two PCs are depicted for RA cases and NYCP controls.(B) Color codes show the Irish contribution to each individual with at least two GP country of origin information in the sample set shown in (A), e.g., the 2GP Irish individuals have 2GP Irish origin and 2GP unknown or USA origin; Not Irish includes only individuals without known Irish ancestry and with at least 2GP information; mixed Irish are those individuals with at least one GP Irish and one GP non-Irish.(C) Analysis using 1,211 ESAIMs selected for differences along PC1 in northern European individuals (see Results).

Mentions: PCA of the “north” only subset showed substantial substructure differences in the distribution of North American Rheumatoid Arthritis (NARAC) cases and controls along the first PC (Figure 4). Importantly, we controlled for this difference in our genome-wide association scan and excluded SNPs that showed association based on this substructure difference [23]. The distribution of individuals in this PC showed a distinct pattern with respect to the context of country of origin information that was available for a subset of control individuals (Figure 4B). Most notably, Irish individuals were distinguished from those of eastern, northern and central European descent. These relationships were further defined by inclusion of additional individuals with the same country of origin genotyped with the 300K SNP set (Table 2). Similar results were also observed using a STRUCTURE analysis of the same dataset (Table 2). The results suggest that the difference in numbers of individuals of Irish ancestry was primarily responsible for the major difference in substructure observed in the NARAC cases and controls [23]. Controlling for this aspect of substructure the λgc in this individual set decreased from 1.15 to 1.07. Since the sample set had a disproportionately large contribution of participants of Irish ancestry we also examined a small set of individuals with nearly proportionate representation of Irish, German, Eastern European, and United Kingdom individuals. Similar to the results on the larger set of individuals, these PCA results showed a west-east gradient (Figure S4). Here however, there was no difference observed between the Irish and UK individuals. Thus, these results further indicate that the number of individuals from each individual group may partially alter relationships among individual groups.


Analysis and application of European genetic substructure using 300 K SNP information.

Tian C, Plenge RM, Ransom M, Lee A, Villoslada P, Selmi C, Klareskog L, Pulver AE, Qi L, Gregersen PK, Seldin MF - PLoS Genet. (2008)

Analysis of European Substructure in Northern European Individuals(A) The first two PCs are depicted for RA cases and NYCP controls.(B) Color codes show the Irish contribution to each individual with at least two GP country of origin information in the sample set shown in (A), e.g., the 2GP Irish individuals have 2GP Irish origin and 2GP unknown or USA origin; Not Irish includes only individuals without known Irish ancestry and with at least 2GP information; mixed Irish are those individuals with at least one GP Irish and one GP non-Irish.(C) Analysis using 1,211 ESAIMs selected for differences along PC1 in northern European individuals (see Results).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2211544&req=5

pgen-0040004-g004: Analysis of European Substructure in Northern European Individuals(A) The first two PCs are depicted for RA cases and NYCP controls.(B) Color codes show the Irish contribution to each individual with at least two GP country of origin information in the sample set shown in (A), e.g., the 2GP Irish individuals have 2GP Irish origin and 2GP unknown or USA origin; Not Irish includes only individuals without known Irish ancestry and with at least 2GP information; mixed Irish are those individuals with at least one GP Irish and one GP non-Irish.(C) Analysis using 1,211 ESAIMs selected for differences along PC1 in northern European individuals (see Results).
Mentions: PCA of the “north” only subset showed substantial substructure differences in the distribution of North American Rheumatoid Arthritis (NARAC) cases and controls along the first PC (Figure 4). Importantly, we controlled for this difference in our genome-wide association scan and excluded SNPs that showed association based on this substructure difference [23]. The distribution of individuals in this PC showed a distinct pattern with respect to the context of country of origin information that was available for a subset of control individuals (Figure 4B). Most notably, Irish individuals were distinguished from those of eastern, northern and central European descent. These relationships were further defined by inclusion of additional individuals with the same country of origin genotyped with the 300K SNP set (Table 2). Similar results were also observed using a STRUCTURE analysis of the same dataset (Table 2). The results suggest that the difference in numbers of individuals of Irish ancestry was primarily responsible for the major difference in substructure observed in the NARAC cases and controls [23]. Controlling for this aspect of substructure the λgc in this individual set decreased from 1.15 to 1.07. Since the sample set had a disproportionately large contribution of participants of Irish ancestry we also examined a small set of individuals with nearly proportionate representation of Irish, German, Eastern European, and United Kingdom individuals. Similar to the results on the larger set of individuals, these PCA results showed a west-east gradient (Figure S4). Here however, there was no difference observed between the Irish and UK individuals. Thus, these results further indicate that the number of individuals from each individual group may partially alter relationships among individual groups.

Bottom Line: A second PC further separated Italian, Spanish, and Greek individuals from those of Ashkenazi Jewish ancestry as well as distinguishing among northern European populations.In addition, two sets of European substructure ancestry informative markers (ESAIMs) were identified that provide substantial substructure information.The results provide further insight into European population genetic substructure and show that this information can be used for improving error rates in association testing of candidate genes and in replication studies of WGA scans.

View Article: PubMed Central - PubMed

Affiliation: Rowe Program in Human Genetics, University of California Davis, Davis, California, United States of America.

ABSTRACT
European population genetic substructure was examined in a diverse set of >1,000 individuals of European descent, each genotyped with >300 K SNPs. Both STRUCTURE and principal component analyses (PCA) showed the largest division/principal component (PC) differentiated northern from southern European ancestry. A second PC further separated Italian, Spanish, and Greek individuals from those of Ashkenazi Jewish ancestry as well as distinguishing among northern European populations. In separate analyses of northern European participants other substructure relationships were discerned showing a west to east gradient. Application of this substructure information was critical in examining a real dataset in whole genome association (WGA) analyses for rheumatoid arthritis in European Americans to reduce false positive signals. In addition, two sets of European substructure ancestry informative markers (ESAIMs) were identified that provide substantial substructure information. The results provide further insight into European population genetic substructure and show that this information can be used for improving error rates in association testing of candidate genes and in replication studies of WGA scans.

Show MeSH
Related in: MedlinePlus