Founder Effect inflates the outcome: The Amish community in Lancaster, PA

Regeneron mildly discloses the use of Lancaster, PA. They mention the inclusion of the Amish, as if it were cautionary and not a disqualification from extrapolating the results to the general population.  Here is an excerpt from the report:


Underdiagnosis and undertreatment of FH continue to be a concern ….

…. the prevalence was 1:256, in line with more recent estimates of 1:217 in Denmark  and 1:319 in the Netherlands. Our assessment of FH prevalence in a U.S. Health care system using this methodology supports the claim that there is significant underdiagnosis of this condition. Whether our estimated prevalence of FH variants in our patient population, largely a stable regional health care population in central Pennsylvania, is generalizable to other U.S. patient populations remains to be determined. We caution that extant familial (and cryptic) relatedness in our study population could result in overestimation of a given FH-causing allele that is rare in the general population, but segregating in family members. For example, our study population was enriched for APOB p.Arg3527Gln, which is known to be common in individuals of Amish descent in Lancaster, Pennsylvania.” ~ Science ( “Genetic identification of familial hypercholesterolemia within a single U.S. health care system,” Dec. 2016, Dewey et al. and Abul-Husn et al. 10.1126/science.aaf6814, p. 10.1126/science.aaf7000

“Caution” is a self-interested disclaimer.

  • The exclusion of any population with founder effect was required and the inclusion invalidates the results.

Instead of highlighting a serious objection, the study euphemized the influence of founder effect with the words, “enriched for APOB.” The Amish have the highest p.Arg3527Gln prevalence on record.[1]  And with the word, “Caution,” this disclosure seems more likely to mitigate objections by this pre-emptive mentioning, than to fully disclose the irrelevance of this study. It takes the edge off of legal and professional criticism. The inclusion of the Amish population and focus on whites of European descent, not to mention the exclusion of the non-whites, warrants a much stronger treatment in Regeneron’s paper than is present.

[1]  Emphasis mine: “This was suggestive of a single mutation transmitted from a common ancestor through the population, with endogamy and genetic drift accounting for its high frequency in the Amish. A prevalence of 1 in 8–9 participants, the highest frequency for APOB p.Arg3527Gln yet recorded, coupled with a strong association with both LDL-cholesterol levels and coronary artery calcification scores, establishes a clear case for the benefits of community screening.” ~ Familial hypercholesterolemia: epidemiology, Neolithic origins and modern geographic distribution, Khemanganee E. Liyanage, et al.