Genomewide Scans of Complex Human Diseases: True Linkage Is Hard to Find

Abstract

Many "complex" human diseases, which involve multiple genetic and environmental determinants, have increased in incidence during the past 2 decades. During the same time period, considerable effort and expense have been expended in whole-genome screens aimed at detection of genetic loci contributing to the susceptibility to complex human diseases. However, the success of positional cloning attempts based on whole-genome screens has been limited, and many of the fundamental questions relating to the genetic epidemiology of complex human disease remain unanswered. Both to review the success of the positional cloning paradigm as applied to complex human disease and to investigate the characteristics of the whole-genome scans undertaken to date, we created a database of 101 studies of complex human disease, which were found by a systematic Medline search (current as of December 2000). We compared these studies, concerning 31 different human complex diseases, with regard to design, methods, and results. The "significance" categorizations proposed by Lander and Kruglyak were used as criteria for the "success" of a study. Most (66.3% [n=67]) of the studies did not show "significant" linkage when the criteria of Lander and Kruglyak (1995) were used, and the results of studies of the same disease were often inconsistent. Our analyses suggest that no single study design consistently produces more-significant results. Multivariate analysis suggests that the only factors independently associated with increased study success are (a) an increase in the number of individuals studied and (b) study of a sample drawn from only one ethnic group. Positional cloning based on whole-genome screens in complex human disease has proved more difficult than originally had been envisioned; detection of linkage and positional cloning of specific disease-susceptibility loci remains elusive.

Genetics of type 1 diabetes mellitus

“…Interestingly, very recent studies suggest that much of the difficulty in mapping T1D susceptibility genes results from inadequate sample sizes and the study of mixed ethnic groups. 21,40 The genes…”

“…However, linkage analysis thus far has had only limited success. 40 Specifically, most studies have failed to generate strong evidence of linkage (except for IDDM1), and those few regions with significant results have proven difficult to replicate (Table 3). Nevertheless, several loci have now been linked to T1D, providing evidence that this disease is a polygenic disorder in most patients studied.…”

Maladies multifactorielles : un cauchemar pour le généticien

“…De récents articles ont souligné que les résultats de très nombreuses études de liaison [7] ou d'association [12] n'ont pu être confirmés. Les causes de ces échecs ont récemment été analysées, et des pistes de recherches pour tenter de sortir de cette situation ont été préco-nisées [13].…”

“…On étudie parfois aussi un caractère situé en amont de la maladie (phénotype intermé-diaire), pour rendre l'analyse plus simple (cas de l'hypercholestérolémie étudiée pour rechercher les gènes impliqués dans l'infarctus du myocarde). En revanche, il est extrêmement difficile d'identifier les gènes de susceptibilité dans les régions chromosomiques repérées par analyse de liaison : ces régions sont effectivement relativement étendues, les allèles de susceptibilité ne sont pas des allèles délétères et, enfin, de nombreux résultats ne sont pas confirmés [7]. L'identification par clonage positionnel est, quant à elle, très rare ; on peut toutefois citer celle du gène CARD15 (NOD2) dans la maladie de Crohn [8] et celle de la région régulatrice des gènes PARK2 et PACRG dans la susceptibilité à la lèpre [9].…”

“…Il est tout à fait vraisemblable qu'il en est de même dans les maladies multifactorielles : pour cette raison, il n'est pas fréquent de retrouver dans de nouvelles études des résultats déjà publiés, qu'il s'agisse d'études de liaison ou d'association [7,12]. L'hétérogénéité allélique peut rendre difficile l'interprétation des études d'association.…”