Finding Rare, Disease-Associated Variants in Isolated Groups: Potential Advantages of Mennonite Populations

Abstract

Large-scale genotyping and next generation sequencing techniques have allowed great advances in the field of molecular genetics. Numerous common variants of low impact have been associated with many complex human traits and diseases, such as bipolar disorder and schizophrenia. Although they may exert a greater impact on risk, few rare disease variants have been found, owing to the greatly increased sample sizes that are typically necessary to demonstrate association with rarer variants. One alternative strategy is to study isolated populations, where historical bottlenecks reduce genetic diversity and some otherwise rare variants may drift to higher frequencies. Here we describe the Mennonite population settlements, considering their history of multiple bottlenecks followed by demographic expansion and a currently widespread geographical distribution. We argue that Mennonite populations are valuable partners for studies seeking to find genetic variants that exert a high impact on risk for a variety of common disorders, including mental illnesses.

Strong Genetic Overlaps Between Dimensional and Categorical Models of Bipolar Disorders in a Family Sample

“…Exclusion criteria included major physical, neurological, or substance use disorders that complicated diagnosis. South American participants all belonged to one of three Mennonite settlements in Brazil who were all descended from a relatively small number of founding couples (Lopes et al, 2016).…”

A study of Kibbutzim in Israel reveals risk factors for cardiometabolic traits and subtle population structure

“…From an evolutionary perspective, rare variants are on average more recent than common variants, and are thus more likely to be disease risk factors. Genetic association studies of common diseases and traits in isolated populations were particularly advantageous for identification of risk loci that are rare in the general population, but possibly enriched or common in an isolated population (Trecartin et al 1981;Baier and L.Hanson 2004;Kristiansson et al 2008;Sabatti et al 2009;Zeggini 2014;Nair and Baier 2015;Fang et al 2016;Gilly et al 2016;Lopes et al 2016;Zeggini et al 2016). The Ashkenazi Jewish (AJ) population has been an attractive population for genetic studies, because of its unique demographic history of a recent severe bottleneck followed by a rapid expansion and monogamy (Guha et al 2012).…”

Clinical characteristics of headaches in an urban Mennonite group in South Brazil

“…1 Genetic drift, reproductive isolation, and at least three bottleneck effects in this population are expected to increase the frequencies of homozygotes and rare alleles, changing the prevalence of chronic diseases. [1][2][3][4] An example of this would be the higher prevalence of dystonia in the Amish, also an Anabaptist population. 5 There are several different subgroups of Mennonites.…”

“…6,7 In contrast, South American Mennonites are still epidemiologically poorly known, despite some advances regarding their genetic heritage. 1,4,8 About three billion people have tension-type headache (TTH) or migraine (1.89 and 1.04 billion, respectively), the most common headaches in the general population. 9 Regarding prevalence, TTH is the third most frequent condition in the world and migraine is the sixth.…”