Risk of severe COVID-19 in patients with inflammatory rheumatic diseases treated with immunosuppressive therapy in Scotland.

OBJECTIVE: To investigate the association of severe coronavirus disease 2019 (COVID-19) in patients with inflammatory rheumatic diseases (IRDs) treated with immunosuppressive drugs. METHOD: A list of 4633 patients on targeted - biological or targeted synthetic - DMARDs in March 2020 was linked to a case-control study that includes all cases of COVID-19 in Scotland. RESULTS: By 22 November 2021, 433 of the 4633 patients treated with targeted DMARDS had been diagnosed with COVID-19, of whom 58 had been hospitalized. With all those in the population not on DMARDs as the reference category, the rate ratio for hospitalized COVID-19 associated with DMARD treatment was 2.14 [95% confidence interval (CI) 2.02-2.26] in those on conventional synthetic (cs) DMARDs, 2.01 (95% CI 1.38-2.91) in those on tumour necrosis factor (TNF) inhibitors as the only targeted agent, and 3.83 (95% CI 2.65-5.56) in those on other targeted DMARDs. Among those on csDMARDs, rate ratios for hospitalized COVID-19 were lowest at 1.66 (95% CI 1.51-1.82) in those on methotrexate and highest at 5.4 (95% CI 4.4-6.7) in those on glucocorticoids at an average dose > 10 mg/day prednisolone equivalent. CONCLUSION: The risk of hospitalized COVID-19 is elevated in IRD patients treated with immunosuppressive drugs compared with the general population. Of these drugs, methotrexate, hydroxychloroquine, and TNF inhibitors carry the lowest risk. The highest risk is associated with prednisolone. A larger study is needed to estimate reliably the risks associated with each class of targeted DMARD.

Modelling the cost-effectiveness of adopting risk-stratified approaches to extended screening intervals in the national diabetic retinopathy screening programme in Scotland.

AIMS: To assess the cost-effectiveness of adopting risk-stratified approaches to extended screening intervals in the national diabetic retinopathy screening programme in Scotland. METHODS: A continuous-time hidden Markov model was fitted to national longitudinal screening data to derive transition probabilities between observed non-referable and referable retinopathy states. These were incorporated in a decision model simulating progression, costs and visual acuity outcomes for a synthetic cohort with a covariate distribution matching that of the Scottish diabetic screening population. The cost-effectiveness of adopting extended (2-year) screening for groups with no observed retinopathy was then assessed over a 30-year time horizon. RESULTS: Individuals with a current grade of no retinopathy on two consecutive screening episodes face the lowest risk of progressing to referable disease. For the cohort as a whole, the incremental cost per quality-adjusted life year gained for annual vs. biennial screening ranged from approximately £74 000 (for those with no retinopathy and a prior observed grade of mild or observable background retinopathy) to approximately £232 000 per quality-adjusted life year gained (for those with no retinopathy on two consecutive screening episodes). The corresponding incremental cost-effectiveness ratios in the subgroup with Type 1 diabetes were substantially lower; approximately £22 000 to £85 000 per quality-adjusted life year gained, respectively. CONCLUSIONS: Biennial screening for individuals with diabetes who have no retinopathy is likely to deliver significant savings for a very small increase in the risk of adverse visual acuity and quality of life outcomes. There is greater uncertainty regarding the long-term cost-effectiveness of adopting biennial screening in younger people with Type 1 diabetes.

Predicted impact of extending the screening interval for diabetic retinopathy: the Scottish Diabetic Retinopathy Screening programme.

AIMS/HYPOTHESIS: The aim of our study was to identify subgroups of patients attending the Scottish Diabetic Retinopathy Screening (DRS) programme who might safely move from annual to two yearly retinopathy screening. METHODS: This was a retrospective cohort study of screening data from the DRS programme collected between 2005 and 2011 for people aged ≥12 years with type 1 or type 2 diabetes in Scotland. We used hidden Markov models to calculate the probabilities of transitions to referable diabetic retinopathy (referable background or proliferative retinopathy) or referable maculopathy. RESULTS: The study included 155,114 individuals with no referable diabetic retinopathy or maculopathy at their first DRS examination and with one or more further DRS examinations. There were 11,275 incident cases of referable diabetic eye disease (9,204 referable maculopathy, 2,071 referable background or proliferative retinopathy). The observed transitions to referable background or proliferative retinopathy were lower for people with no visible retinopathy vs mild background retinopathy at their prior examination (respectively, 1.2% vs 8.1% for type 1 diabetes and 0.6% vs 5.1% for type 2 diabetes). The lowest probability for transitioning to referable background or proliferative retinopathy was among people with two consecutive screens showing no visible retinopathy, where the probability was <0.3% for type 1 and <0.2% for type 2 diabetes at 2 years. CONCLUSIONS/INTERPRETATION: Transition rates to referable diabetic eye disease were lowest among people with type 2 diabetes and two consecutive screens showing no visible retinopathy. If such people had been offered two yearly screening the DRS service would have needed to screen 40% fewer people in 2009.

Association of ANXA11 genetic variation with sarcoidosis in African Americans and European Americans.

A recent genome-wide association study in a German population and two subsequent studies in European populations found that a non-synonymous single-nucleotide polymorphism (SNP), rs1049550, within the annexin A11 (ANXA11) gene was associated with susceptibility to sarcoidosis. We sought to identify additional ANXA11 variants independently associated with sarcoidosis, determine whether any sarcoidosis-associated ANXA11 variants were associated with chest radiographic phenotypes, and explore human leukocyte antigen (HLA) SNP-SNP interactions with ANXA11. A total of 209 SNPs spanning 100 kb including the 5' promoter, coding, and 3' untranslated regions of ANXA11 were genotyped for 1689 sarcoidosis cases and 1252 controls. After adjustment for rs1049550, two additional novel ANXA11 sarcoidosis associations were identified only in African Americans--rs61860052 (odds ratio (OR)=0.62; 95% confidence interval (CI)=0.40-0.97) and rs4377299 (OR=1.31; 95% CI=1.06-1.63). These associations were more pronounced in radiologically-classified Scadding stage IV sarcoidosis cases. We also identified a significant SNP-SNP interaction between rs1049550 and a sarcoidosis risk SNP (rs9268839) near the HLA-DRA locus. This further genetic dissection of ANXA11 may provide additional insight into the immune dysregulation characteristic of sarcoidosis pathophysiology.

Hospitalised hip fracture risk with rosiglitazone and pioglitazone use compared with other glucose-lowering drugs.

AIMS/HYPOTHESIS: Current drug labels for thiazolidinediones (TZDs) warn of increased fractures, predominantly for distal fractures in women. We examined whether exposure to TZDs affects hip fracture in women and men and compared the risk to that found with other drugs used in diabetes. METHODS: Using a nationwide database of prescriptions, hospital admissions and deaths in those with type 2 diabetes in Scotland we calculated TZD exposure among 206,672 individuals. Discrete-time failure analysis was used to model the effect of cumulative drug exposure on hip fracture during 1999-2008. RESULTS: There were 176 hip fractures among 37,479 exposed individuals. Hip fracture risk increased with cumulative exposure to TZD: OR per year of exposure 1.18 (95% CI 1.09, 1.28; p = 3 × 10(-5)), adjusted for age, sex and calendar month. Hip fracture increased with cumulative exposure in both men (OR 1.20; 95% CI 1.03, 1.41) and women (OR 1.18; 95% CI 1.07, 1.29) and risks were similar for pioglitazone (OR 1.18) and rosiglitazone (OR 1.16). The association was similar when adjusted for exposure to other drugs for diabetes and for other potential confounders. There was no association of hip fracture with cumulative exposure to sulfonylureas, metformin or insulin in this analysis. The 90-day mortality associated with hip fractures was similar in ever-users of TZD (15%) and in never-users (13%). CONCLUSIONS/INTERPRETATION: Hip fracture is a severe adverse effect with TZDs, affecting both sexes; labels should be changed to warn of this. The excess mortality is at least as much as expected from the reported association of pioglitazone with bladder cancer.

Genome-wide association and meta-analysis in populations from Starr County, Texas, and Mexico City identify type 2 diabetes susceptibility loci and enrichment for expression quantitative trait loci in top signals.

AIMS/HYPOTHESIS: We conducted genome-wide association studies (GWASs) and expression quantitative trait loci (eQTL) analyses to identify and characterise risk loci for type 2 diabetes in Mexican-Americans from Starr County, TX, USA. METHOD: Using 1.8 million directly interrogated and imputed genotypes in 837 unrelated type 2 diabetes cases and 436 normoglycaemic controls, we conducted Armitage trend tests. To improve power in this population with high disease rates, we also performed ordinal regression including an intermediate class with impaired fasting glucose and/or glucose tolerance. These analyses were followed by meta-analysis with a study of 967 type 2 diabetes cases and 343 normoglycaemic controls from Mexico City, Mexico. RESULT: The top signals (unadjusted p value <1 × 10(-5)) included 49 single nucleotide polymorphisms (SNPs) in eight gene regions (PER3, PARD3B, EPHA4, TOMM7, PTPRD, HNT [also known as RREB1], LOC729993 and IL34) and six intergenic regions. Among these was a missense polymorphism (rs10462020; Gly639Val) in the clock gene PER3, a system recently implicated in diabetes. We also report a second signal (minimum p value 1.52 × 10(-6)) within PTPRD, independent of the previously implicated SNP, in a population of Han Chinese. Top meta-analysis signals included known regions HNF1A and KCNQ1. Annotation of top association signals in both studies revealed a marked excess of trans-acting eQTL in both adipose and muscle tissues. CONCLUSIONS/INTERPRETATION: In the largest study of type 2 diabetes in Mexican populations to date, we identified modest associations of novel and previously reported SNPs. In addition, in our top signals we report significant excess of SNPs that predict transcript levels in muscle and adipose tissues.

Genome-wide association study of type 2 diabetes in a sample from Mexico City and a meta-analysis of a Mexican-American sample from Starr County, Texas.

AIMS/HYPOTHESIS: We report a genome-wide association study of type 2 diabetes in an admixed sample from Mexico City and describe the results of a meta-analysis of this study and another genome-wide scan in a Mexican-American sample from Starr County, TX, USA. The top signals observed in this meta-analysis were followed up in the Diabetes Genetics Replication and Meta-analysis Consortium (DIAGRAM) and DIAGRAM+ datasets. METHODS: We analysed 967 cases and 343 normoglycaemic controls. The samples were genotyped with the Affymetrix Genome-wide Human SNP array 5.0. Associations of genotyped and imputed markers with type 2 diabetes were tested using a missing data likelihood score test. A fixed-effects meta-analysis including 1,804 cases and 780 normoglycaemic controls was carried out by weighting the effect estimates by their inverse variances. RESULTS: In the meta-analysis of the two Hispanic studies, markers showing suggestive associations (p < 10(-5)) were identified in two known diabetes genes, HNF1A and KCNQ1, as well as in several additional regions. Meta-analysis of the two Hispanic studies and the recent DIAGRAM+ dataset identified genome-wide significant signals (p < 5 × 10(-8)) within or near the genes HNF1A and CDKN2A/CDKN2B, as well as suggestive associations in three additional regions, IGF2BP2, KCNQ1 and the previously unreported C14orf70. CONCLUSIONS/INTERPRETATION: We observed numerous regions with suggestive associations with type 2 diabetes. Some of these signals correspond to regions described in previous studies. However, many of these regions could not be replicated in the DIAGRAM datasets. It is critical to carry out additional studies in Hispanic and American Indian populations, which have a high prevalence of type 2 diabetes.

A genome-wide admixture scan for ancestry-linked genes predisposing to sarcoidosis in African-Americans.

Genome-wide linkage and association studies have uncovered variants associated with sarcoidosis, a multiorgan granulomatous inflammatory disease. African ancestry may influence disease pathogenesis, as African-Americans are more commonly affected by sarcoidosis. Therefore, we conducted the first sarcoidosis genome-wide ancestry scan using a map of 1384 highly ancestry-informative single-nucleotide polymorphisms genotyped on 1357 sarcoidosis cases and 703 unaffected controls self-identified as African-American. The most significant ancestry association was at marker rs11966463 on chromosome 6p22.3 (ancestry association risk ratio (aRR)=1.90; P=0.0002). When we restricted the analysis to biopsy-confirmed cases, the aRR for this marker increased to 2.01; P=0.00007. Among the eight other markers that demonstrated suggestive ancestry associations with sarcoidosis were rs1462906 on chromosome 8p12, which had the most significant association with European ancestry (aRR=0.65; P=0.002), and markers on chromosomes 5p13 (aRR=1.46; P=0.005) and 5q31 (aRR=0.67; P=0.005), which correspond to regions we previously identified through sib-pair linkage analyses. Overall, the most significant ancestry association for Scadding stage IV cases was to marker rs7919137 on chromosome 10p11.22 (aRR=0.27; P=2 × 10(-5)), a region not associated with disease susceptibility. In summary, through admixture mapping of sarcoidosis we have confirmed previous genetic linkages and identified several novel putative candidate loci for sarcoidosis.

The prevalence, correlates and impact of dementia in Cuba. A 10/66 group population-based survey.

BACKGROUND: We aimed to estimate the prevalence, correlates and impact of dementia in Havana and Matanzas, Cuba. METHODS: A 1-phase catchment area survey of all over 65-year-old residents of 7 catchment areas in Havana and 1 in Matanzas was conducted. Dementia diagnosis was established according to DSM-IV and our own, pre-validated 10/66 criteria. The impact of dementia was assessed through associations with needs for care, cutting back on work to care and caregiver psychological morbidity. RESULTS: We interviewed 2,944 older people, a response proportion of 96.4%. The prevalence of DSM-IV dementia was 6.4% and that of 10/66 dementia 10.8%. Both dementia outcomes were associated with older age, less education, a family history of dementia, shorter leg length and smaller skull circumference. Dementia, rather than physical health problems or depression, was the main contributor to needs for care (population-attributable prevalence fraction = 64.6%) and caregiver cutting back on work (population-attributable prevalence fraction = 57.3%). CONCLUSION: The prevalence of dementia in Cuba is similar to Europe. Among health conditions, dementia is the major contributor to dependency and caregiver economic and psychological strain. More attention needs to be given to it and other chronic diseases associated more with disability than premature mortality.

Ethnic differences in retinal microvascular structure.

AIMS/HYPOTHESIS: People of African origin have increased risk of stroke and retinal microvascular disease compared with populations of European origin. We compared quantitative measures of retinal microvasculature in British white Europeans and African Caribbeans. METHODS: Population-based study of 215 (45% male) British African-Caribbean migrants and 323 (48% male) white Europeans aged 40-69 years. Digitised retinal images were analysed using a validated semi-automated system. RESULTS: Arteriolar optimality deviation, an indicator of endothelial dysfunction, was greater in African Caribbeans (age- and sex-adjusted means [95% CIs]: 0.06 [0.05-0.06] vs 0.04 [0.04-0.05], p = 0.004); this was unexplained by conventional risk factors. Arteriolar diameters were narrower in African Caribbeans (age- and sex-adjusted means [95% CIs]: 18.4 [18.1-18.6] vs 17.9 [17.6-18.2], p = 0.011). These ethnic differences in diameters were attenuated on adjustment for systolic BP (SBP) (adjusted means: 18.2 vs 18.1, p = 0.31). However, there was a significant interaction (p = 0.011) between diabetes and SBP, such that SBP was strongly associated with arteriolar diameter in people without diabetes, but not in those with diabetes (adjusted beta-coefficients for SBP: Europeans: -0.42, p = 0.002 vs 0.17, p = 0.69, African Caribbeans: -0.35, p = 0.023 vs 0.01, p = 0.96). Other measures of retinal vasculature did not differ by ethnicity. CONCLUSIONS/INTERPRETATION: British African Caribbeans appear to have poorer retinal arteriolar endothelial function than white Europeans. Higher BPs explained the narrower arterioles in African Caribbeans; however, patterns of association between arteriolar narrowing and BP suggest the possibility that cerebral autoregulation and/or remodelling might be adversely affected by diabetes in both ethnic groups.

Cardiovascular disease mortality in relation to childhood and adulthood socioeconomic markers in British South Asian men.

OBJECTIVE: To study the effects of childhood and adulthood socioeconomic position (SEP) including length of education on rates of cardiovascular disease (CVD) mortality in British South Asians. DESIGN: Cross-sectional study with ongoing mortality follow-up. SETTING: West London Borough of Ealing, population-based study. PATIENTS: 1400 South Asian men (52% Punjabi Sikh origin) aged 40-69, first studied 1988-1990 and followed for mortality to October 2006. MAIN OUTCOME MEASURES: Deaths due to cardiovascular disease. RESULTS: 143 men have died from CVD. Men in non-manual adult occupations were less likely to die from CVD than those in unskilled manual occupations (age-adjusted hazard ratio (HR) 0.55 (95% CI 0.35 to 0.88)). Men with 11+ years of education had reduced risk compared with those with <11 years of education (HR 0.66 (95% CI 0.47 to 0.94)). Men who had both non-manual occupations and 11+ years of education were less likely to die from CVD (15 deaths, 282 men; HR 0.39, 95% CI 0.21 to 0.73) than those who were most socially disadvantaged during childhood and adulthood (27 deaths, 187 men). These associations remained after adjustment for other markers of SEP, lifestyle and conventional risk factors. Similar, but weaker, associations were observed when paternal occupation defined childhood SEP. CONCLUSIONS: Years of education, and to a lesser extent paternal occupation, as markers of childhood SEP, had cumulative effects with adulthood socioeconomic circumstances on risk of CVD death; these cumulative effects were strongest in men whose own occupation was non-manual and were unexplained by conventional risk factors measured in middle age.

The Prevalence, Correlates and Impact of Dementia in Cuba

We aimed to estimate the prevalence, correlates and impact of dementia in Havana and Matanzas, Cuba. Methods: A 1-phase catchment area survey of all over 65-year-old residents of 7 catchment areas in Havana and 1 in Matanzas was conducted. Dementia diagnosis was established according to DSM-IV and our own, pre-validated10/66 criteria. The impact of dementia was assessed through associations with needs for care, cutting back on work to care and caregiver psychological morbidity...(AU)

MGEA5-14 polymorphism and type 2 diabetes in Mexico City.

A family-based study has recently reported that a variant located in intron 10 of the gene MGEA5 increases susceptibility to Type 2 Diabetes (T2D). We evaluated the distribution of this SNP in a sample of T2D patients (N = 271) and controls (N = 244) from Mexico City. The frequency of the T allele was higher in the cases (2.6%) than in the controls (1.8%). After adjusting for age, sex, BMI, education, and individual ancestry the odds ratio was 1.60 but the 95% confidence interval was wide and overlapped 1 (0.52-4.86, P-value : 0.404). In order to characterize the distribution of the MGEA5-14 polymorphism in the relevant parental populations, we genotyped this variant in European (and European Americans), West African, and Native American samples. The T-allele was present at a frequency of 2.3% in Spain, 4.2% in European Americans, and 13% in Western Africans, but was absent in two Native American samples from Mexico and Peru. Given the low frequency of the T-allele, further studies using large sample sizes will be required to confirm the role of this variant in T2D.

Association of TCF7L2 polymorphisms with type 2 diabetes in Mexico City.

Polymorphisms within the transcription factor 7-like 2 gene (TCF7L2) have been associated with type 2 diabetes (T2D) in several recent studies. We characterized three of these polymorphisms (rs12255372, rs7903146 and the microsatellite DG10S478) in an admixed sample of 286 patients with T2D and 275 controls from Mexico City. We also analyzed three samples representative of the relevant parental populations: Native Americans from the state of Guerrero (Mexico), Spanish from Valencia and Nigerians (Bini from the Edo region). In order to minimize potential confounding because of the presence of population stratification in the sample, we evaluated the association of the three TCF7L2 polymorphisms with T2D by using the program admixmap to fit a logistic regression model incorporating individual ancestry, sex, age, body mass index and education. The markers rs12255372, rs7903146 and DG10S478 are in tight disequilibrium in the Mexican sample. We observed a significant association between the single-nucleotide polymorphism (SNP) rs12255372 and the microsatellite DG10S478 with T2D in the Mexican sample [rs12255372, odds ratio (OR) = 1.78, p = 0.017; DG10S478, OR = 1.62, p = 0.041]. The SNP rs7903146 shows similar trends, but its association with T2D is not as strong (OR = 1.39, p = 0.152). Analysis of the parental samples, as well as other available data, indicates that there are substantial population frequency differences for these polymorphisms: The frequencies of the T2D risk factors are more than 20% higher in European and West African populations than in East Asian and Native American populations.

Systemic lupus erythematosus: genes versus environment in high risk populations.

The risks of systemic lupus erythematosus (SLE) are known to vary considerably with ethnic origin. Prevalence of lupus is increased in African-American, Afro-Caribbean, Native American, Asian Indian, Polynesian and Chinese populations compared with people of European descent. The consistency with which high prevalence of lupus occurs in these populations descent living in different environments suggests that genetic factors are likely to underlie the high risk in this group. However the increased risk of lupus in high risk groups such as West Africans compared with Europeans does not appear to be accounted for by differences in allele frequencies at any of the loci where associations with SLE have been found, including those in the HLA region. To date the contribution of environmental factors to a complex disease such as lupus is still not fully understood. This article explores possible environmental risk factors for SLE in high risk ethnic groups. Smoking, occupational exposures to silica and exposure to infection in childhood may explain some non-genetic risk factors for SLE in these groups.

Do known risk factors explain the higher coronary heart disease mortality in South Asian compared with European men? Prospective follow-up of the Southall and Brent studies, UK.

AIMS/HYPOTHESIS: We examined prospectively whether measured risk factors can explain the higher CHD mortality in South Asians compared with Europeans. MATERIALS AND METHODS: Conventional CHD risk factors and those associated with insulin resistance were measured in 1,787 European and 1,420 South Asian men aged 40 to 69 years at baseline in the population-based Southall and Brent studies (London) between 1988 and 1990. Participants were followed up for mortality. RESULTS: By February 2006, there were 202 CHD deaths (108 Asian, 94 European). South Asian men had double the CHD mortality of European men in Cox regression analyses adjusted for age, smoking, and cholesterol (hazard ratio [HR] 2.14, 95% CI 1.56-2.94, p<0.001). Nearly half of all South Asian CHD deaths versus 13% of deaths among Europeans were among persons with diabetes. Asian men had greater CHD mortality than Europeans, both in the with- and the without-diabetes categories at baseline. CHD mortality remained significantly higher in South Asian men in multivariable models that adjusted for conventional risk factors and diabetes and/or impaired glucose regulation, features of insulin resistance, or the metabolic syndrome (HR 1.6-1.9). Accounting for co-morbidity and socio-economic status did not materially alter the findings. CONCLUSIONS/INTERPRETATION: These data confirm that South Asian men have significantly higher CHD mortality than their European counterparts, while indicating that neither conventional risk factors, nor insulin resistance parameters or metabolic syndrome criteria as currently defined can account for this excess risk. The contribution of unmeasured factors to the elevated vascular risk in South Asians should be addressed in future studies.

Metabolic syndrome and coronary heart disease in South Asians, African-Caribbeans and white Europeans: a UK population-based cross-sectional study.

AIMS/HYPOTHESIS: The aim of this study was to study differences in the prevalence of the metabolic syndrome and its associations with prevalent CHD according to ethnicity and sex. METHODS: We performed a combined analysis of two population-based cross-sectional studies conducted between 1988 and 1991 that followed identical protocols. Participants (aged 40-69 years) comprised 2,346 Europeans (76% male), 1,711 South Asians (83% male) and 803 African-Caribbeans (57% male) resident in west London. Fasting blood, overnight urine collection, clinical and anthropometric measurements were performed. Clinical history or major ECG changes defined prevalent CHD. The metabolic syndrome was defined according to the criteria recommended by the World Health Organization (WHO) and the National Cholesterol Education Programme (NCEP). RESULTS: The prevalence of the metabolic syndrome was highest in South Asians (WHO, men 46%, women 31%; NCEP, men 29%, women 32%) and lowest in European women (WHO, 9%; NCEP, 14%). The prevalence of CHD was 10% in South Asian men, 9% in European men, 5-6% in African-Caribbeans and European women, and 2% in South Asian women. The metabolic syndrome was associated with prevalent CHD in European men [NCEP, odds ratio (OR)=1.6, 95% CI 1.2-2.4; WHO, OR=1.7, 95% CI 1.2-2.5] and South Asian men (NCEP, OR=2.1, 95% CI 1.5-3.1; WHO, OR=1.6, 95% CI 1.1-2.3). Associations with CHD were weaker in African-Caribbeans and were inconsistent among European women. CONCLUSIONS/INTERPRETATION: The current definitions of the metabolic syndrome give an inconsistent picture of cardiovascular disease risk when applied to different ethnic groups within the UK. Prospective studies are needed to validate workable ethnic-specific definitions.

Design and analysis of admixture mapping studies.

Admixture between populations originating on different continents can be exploited to detect disease susceptibility loci at which risk alleles are distributed differentially between these populations. We first examine the statistical power and mapping resolution of this approach in the limiting situation in which gamete admixture and locus ancestry are measured without uncertainty. We show that, for a rare disease, the most efficient design is to study affected individuals only. In a typical African American population (two-way admixture proportions 0.8/0.2, ancestry crossover rate 2 per 100 cM), a study of 800 affected individuals has 90% power to detect at P values <10(-5) a locus that generates a risk ratio of 2 between populations, with an expected mapping resolution (size of 95% confidence region for the position of the locus) of 4 cM. In practice, to infer locus ancestry from marker data requires Bayesian computationally intensive methods, as implemented in the program ADMIXMAP. Affected-only study designs require strong prior information on the frequencies of each allele given locus ancestry. We show how data from unadmixed and admixed populations can be combined to estimate these ancestry-specific allele frequencies within the admixed population under study, allowing for variation between allele frequencies in unadmixed and admixed populations. Using simulated data based on the genetic structure of the African American population, we show that 60% of information can be extracted in a test for linkage using markers with an ancestry information content of 36% at 3-cM spacing. As in classic linkage studies, the most efficient strategy is to use markers at a moderate density for an initial genome search and then to saturate regions of putative linkage with additional markers, to extract nearly all information about locus ancestry.