Genetic variability of HLA in the Dariusleut Hutterites. A comparative genetic analysis of the Hutterities, the Amish, and other selected Caucasian populations.

There are three endogamous subdivisions of the Hutterite population, a North American religious isolate. These individuals live on communal farms, and residence is strictly patrilocal. We report on the distributions of HLA-A and B alleles and haplotypes in 203 married women from one subdivision--the Dariusleut--in Alberta, Canada. We demonstrate that there is significant linkage disequilbrium among a large fraction of the distinct haplotypes in the Dariusleut Hutterite data; there is a restriction in the number of distinct haplotypes present in the Dariusleut; the Hutterites and the Old Order Amish (Lancaster County, Pennsylvania) are the most genetically distant pair of populations in an ensemble of 11 Caucasian populations; and, finally, the Old Order Amish and the Hutterites are approximately as distant from the Indiana Amish as they are from the eight other Caucasian populations, which are tightly clustered in the space of gene frequencies. These results are consistent with the fact that the Amish and the Hutterites are genetic isolates with small numbers of founders. Certain haplotypes show significant linkage disequilibrium in these as well as in other Caucasian samples. Thus, some of the linkage disequilibrium antedates the formation of these Anabaptist sects.     

Seasonality of births in South-Eastern Nigeria.

A study of seasonal pattern of births in Nigeria was conducted using data on live births for the period 1971-76 from 4 climatically similar southeastern states (Anambra, Imo, Cross River and Rivers State). After pooling the data, the monthly distribution for different years was calculated. The resulting time series was graphically compared with temperature levels during time of conception, or nine months back. Data analysis revealed a seasonal pattern in the monthly distribution of births, with the peak period observed during April-June, and a trough during November-January. Counting 9 months back, the conceptions were calculated as occuring during July, August, or September of the previous year. In terms of the annual agricultural cycle of the southeastern states, July-September corresponded with the period of light farm work or relative idleness for men (main activity during this period is weeding and tending the crops, tasks primarily done by women and children); this is also a period of abundance of fruits, vegetables and palm wine, and rains after dusk, conditions conducive to mating.     

Linkage of bipolar affective disorders to markers on chromosome 11p is excluded in a second lateral extension of Amish pedigree 110.

Linkage between markers on chromosome 11p and bipolar affective disorders can be excluded in a second large lateral extension of the original Amish Pedigree 110. These results, together with previous negative linkage findings, suggest that there is not one single gene on 11p conferring susceptibility for bipolar affective disorders among the Old Order Amish.     

The Old Order Amish: Lessons From Kansas Ethnography

Abstract

Although they are widely known in the United States, the Old Order Amish present a puzzling face to both social science and popular media. This puzzle can be seen to arise from inaccurate notions of Amish life and an inadequate analytical paradigm for Amish ethnicity. ‘Both these features are especially evident in the case of the Amish of central Kansas; research in this area suggests that the fundamental sources of Amish distinctiveness are cultural rather than social and independent of technological backwardness of social isolation     

Effects of maternal birth season on birth seasonality in the Canadian population during the seventeenth and eighteenth centuries

Birth records of the French-Canadian population for the period 1621-1765 were analyzed retrospectively to examine the effect of maternal birth season on the seasonal distribution of births. Preliminary examination indicated that there was a bimodal pattern in birth seasonality: a major peak in early spring, a trough in early summer, a minor peak in autumn, and a trough around December. Because this seasonality was strongly biased at the level of the first birth by the month of marriage, which was concentrated in November, the seasonality of nonfirst births (n = 32,926) was examined in relation to the four seasons of maternal birth. Mothers born in May-July showed a flatter monthly distribution of nonfirst births at a maternal age of 28 years or more. Analysis of marriage-first birth intervals indicated that mothers who married in August-October showed a lower percentage of immediate conception (intervals of 8-10 months), whereas those mothers born in May-July had a higher percentage of immediate conception. This difference in birth seasonality shown by mothers born in May-July is similar to results from early twentieth-century Japan. Some seasonal infertility factors could have affected the embryos at the earliest stage of pregnancy, modifying a part of the seasonal variation in birth rate.     

Blood groups in two Amish demes

Blood group studies in two Old Order Amish isolates support previous evidence for genetic differences in the two groups. The more completely studied Amish community, that of Lancaster Co., Pa., revealed higher A and lower O phenotype frequencies than found in the Amish of Holmes Co., Ohio. In both groups, about one-fourth of individuals are Rh negative. Three blood group genes (Kell-positive, CD^ue and CDE) are present in low frequency in the Lancaster Amish, and pedigree studies identified individuals who may have introduced them to the Amish. Preliminary studies of an unusual antibody found in one Amish female provide evidence for a new red cell antigen which is present in about one-fourth of Americans.     

A novel nemaline myopathy in the Amish caused by a mutation in troponin T1

The nemaline myopathies are characterized by weakness and eosinophilic, rodlike (nemaline) inclusions in muscle fibers. Amish nemaline myopathy is a form of nemaline myopathy common among the Old Order Amish. In the first months of life, affected infants have tremors with hypotonia and mild contractures of the shoulders and hips. Progressive worsening of the proximal contractures, weakness, and a pectus carinatum deformity develop before the children die of respiratory insufficiency, usually in the second year. The disorder has an incidence of approximately 1 in 500 among the Amish, and it is inherited in an autosomal recessive pattern. Using a genealogy database, automated pedigree software, and linkage analysis of DNA samples from four sibships, we identified an approximately 2-cM interval on chromosome 19q13.4 that was homozygous in all affected individuals. The gene for the sarcomeric thin-filament protein, slow skeletal muscle troponin T (TNNT1), maps to this interval and was sequenced. We identified a stop codon in exon 11, predicted to truncate the protein at amino acid 179, which segregates with the disease. We conclude that Amish nemaline myopathy is a distinct, heritable, myopathic disorder caused by a mutation in TNNT1.     

Genetic mapping of glutaric aciduria, type 3, to chromosome 7 and identification of mutations in c7orf10

While screening Old Order Amish children for glutaric aciduria type 1 (GA1) between 1989 and 1993, we found three healthy children who excreted abnormal quantities of glutaric acid but low 3-hydroxyglutaric acid, a pattern consistent with glutaric aciduria type 3 (GA3). None of these children had the GCDH c.1262C→T mutation that causes GA1 among the Amish. Using single-nucleotide polymorphism (SNP) genotypes, we identified a shared homozygous 4.7 Mb region on chromosome 7. This region contained 25 genes including C7orf10, an open reading frame with a putative mitochondrial targeting sequence and coenzyme-A transferase domain. Direct sequencing of C7orf10 revealed that the three Amish individuals were homozygous for a nonsynonymous sequence variant (c.895C→T, Arg299Trp). We then sequenced three non-Amish children with GA3 and discovered two nonsense mutations (c.322C→T, Arg108Ter, and c.424C→T, Arg142Ter) in addition to the Amish mutation. Two pathogenic alleles were identified in each of the six patients. There was no consistent clinical phenotype associated with GA3. In affected individuals, urine molar ratios of glutarate to its derivatives (3-hydroxyglutarate, glutarylcarnitine, and glutarylglycine) were elevated, suggesting impaired formation of glutaryl-CoA. These observations refine our understanding of the lysine-tryptophan degradation pathway and have important implications for the pathophysiology of GA1.     

Ostracism on trial: The limits of individual rights

In 1947, a case of ostracism was tried in the Common Pleas Court of Wooster, county seat of Wayne County, Ohio. The plaintiff, Andrew J. Yoder, filed suit against an old Order Amish Bishop and two preachers asking for $40,000 in damages and a court injunction against a “boycott” that he alleged had been organized against hin throughout the Amish Church. The verdict was based on a concept of justice embodied inthe “reasonable man” doctrine. The jury intended to remedy severe“injustice” inflicted on the petitioner, a former member of the Old Order Amish Church, represented by the bishop and the preachers. The defendants, on the other hand, were steadfast in their belief that their actions were in compliance with the commandments of God— God's justice could not be questioned. This “Meidung” case, a public dispute between Amish mores and American Civil Law, could not solve the underlying issue of conflicting values. The trial led to results that were distasteful to the contesting parties, as well as to the jury, the presiding judge, the officials involved in executing the verdict, and the general public.     

A Method to Prioritize Quantitative Traits and Individuals for Sequencing in Family-Based Studies

Owing to recent advances in DNA sequencing, it is now technically feasible to evaluate the contribution of rare variation to complex traits and diseases. However, it is still cost prohibitive to sequence the whole genome (or exome) of all individuals in each study. For quantitative traits, one strategy to reduce cost is to sequence individuals in the tails of the trait distribution. However, the next challenge becomes how to prioritize traits and individuals for sequencing since individuals are often characterized for dozens of medically relevant traits. In this article, we describe a new method, the Rare Variant Kinship Test (RVKT), which leverages relationship information in family-based studies to identify quantitative traits that are likely influenced by rare variants. Conditional on nuclear families and extended pedigrees, we evaluate the power of the RVKT via simulation. Not unexpectedly, the power of our method depends strongly on effect size, and to a lesser extent, on the frequency of the rare variant and the number and type of relationships in the sample. As an illustration, we also apply our method to data from two genetic studies in the Old Order Amish, a founder population with extensive genealogical records. Remarkably, we implicate the presence of a rare variant that lowers fasting triglyceride levels in the Heredity and Phenotype Intervention (HAPI) Heart study (p = 0.044), consistent with the presence of a previously identified null mutation in the APOC3 gene that lowers fasting triglyceride levels in HAPI Heart study participants.     

Linkage Analyses of Chromosome 18 Markers Do Not Identify a Major Susceptibility Locus for Bipolar Affective Disorder in the Old Order Amish

Previously reported linkage of bipolar affective disorder to DNA markers in the pericentromeric region of chromosome 18 was reexamined in a larger homogeneous sample of Old Order Amish families. Four markers (D18S21, D18S53, D18S44, and D18S40) were examined in three kindreds containing 31 bipolar I (BP I) individuals. Although linkage findings were replicated in the one previously studied Amish pedigree containing four BP I individuals, linkage to this region was excluded in the larger sample. If a susceptibility locus for bipolar disorder is located in this region of chromosome 18, it is of minor significance in this population.     

Status of the search for a major genetic locus for affective disorder in the Old Order Amish

Summary We have resumed the search for an autosomal linkage with affective disorder in the Old Order Amish and report the pairwise linkage results after screening 185 marked loci. No positive evidence of genetic linkage was found, and we estimate that roughly 23% of the autosomal genome has been excluded from linkage.     

Cystic fibrosis in the Ohio Amish: Gene frequency and founder effect

A high incidence of cystic fibrosis (CF), 1/569 live births (0.00176), was found among 10 816 live births in an Ohio Amish isolate. The minimum gene frequency calculated from this incidence was 0.042. In marked contrast, a second Amish isolate was described with no occurrence of CF among 4448 live births. Founder effect is the most probable explanation for the difference in the CF gene frequency between the two communities. Pedigree analysis identified a single ancestral couple born in the 1700s common to all obligate heterozygotes.     

Erythrocyte pyruvate kinase deficiency in the Ohio Amish: origin and characterization of the mutant enzyme

We have identified eight individuals in an Amish population in Geauga County, Ohio, who have a congenital hemolytic anemia and red cell pyruvate kinase (PK) deficiency. The mutant enzyme is a low Km phosphoenolpyruvate (PEP) variant associated with a slower (77.5% of normal) electrophoretic mobility in starch gel. Because of the high consanguinity in this population, we assume the affected individuals are homozygous for the mutant gene. Genealogical records allow us to trace all eight cases back to a common ancestor who lived in Mifflin County, Pennsylvania. His sister was a common ancestor to all cases of PK deficiency originally described in the Pennsylvania Amish isolate. Therefore, all cases of PK deficiency in the Amish arose from a common ancestral pair.     

Genetic homogeneity of cartilage-hair hypoplasia

Cartilage-hair hypoplasia (CHH) is an autosomal recessive metaphyseal chondrodysplasia characterized by short stature and hypoplasia of the hair. Associated pleiotropic features include deficient erythrogenesis, impaired T-cell mediated immunity, Hirschsprung's disease, and an increased risk of malignancies. CHH is most prevalent among the Old Order Amish in the United States and among the Finns, but sporadic families have been described among many other populations. We have previously mapped the gene for CHH to the short arm of chromosome 9 in Finnish and Amish families. The CHH locus resides close to D9S163 within an interval of 1.5 cM flanked by D9S165 and D9S50. In order to investigate the genetic homogeneity of CHH in various populations, we studied nine families with no genealogical connections to either Amish or Finns. No recombinants were detected between the CHH gene and any of the three closest marker loci studied, suggesting that CHH in these families results from mutation(s) at the same locus as in the Amish and Finnish families.     

Birth seasonality in the early Spanish-Mexican colonists of California (1769-1898)

The pattern of birth seasonality in California's early Spanish-Mexican colonists between 1769 and 1898 was reconstructed using genealogical data for progeny of 657 marriages. The monthly distribution of the 3,824 births in this sample shows a strong seasonal pattern, with spring and fall peaks (corresponding to peaks in conceptions during July and February) and a low point in October. This seasonal reproductive pattern is the result of a complicated set of interactions among environmental, physiological, and cultural variables. California's strongly developed winter rainfall pattern and the 19th-century agricultural cycle clearly influenced the seasonal pattern of marriages and births in this agrarian society. Several historical processes interacted with these environmental and economic factors to transform the seasonal birth pattern of the early colonists. Through time the birth pattern becomes less variable and the birth maximum shifts from spring to early winter. This appears to be, at least in part, a result of changes in labor patterns and an increase in average parity. These data suggest a multifactorial explanation for birth seasonality, in which the timing of conceptions and births is influenced by both environmental and socioeconomic factors.     

Maternal lineages and Alzheimer disease risk in the Old Order Amish

Old Order Amish, founded by a small number of Swiss immigrants, exist in culturally isolated communities across rural North America. The consequences of genetic isolation and inbreeding within this group are evident by increased frequencies of many monogenic diseases and several complex disorders. Conversely, the prevalence of Alzheimer disease (AD), the most common form of dementia, is lower in the Amish than in the general American population. Since mitochondrial dysfunction has been proposed as an underlying cause of AD and a specific haplogroup was found to affect AD susceptibility in Caucasians, we investigated whether inherited mitochondrial haplogroups affect risk of developing AD dementia in Ohio and Indiana Amish communities. Ninety-five independent matrilines were observed across six large pedigrees and three small pedigrees then classified into seven major European haplogroups. Haplogroup T is the most frequent haplogroup represented overall in these maternal lines (35.4%) while observed in only 10.6% in outbred American and European populations. Furthermore, haplogroups J and K are less frequent (1.0%) than in the outbred data set (9.4–11.2%). Affected case matrilines and unaffected control lines were chosen from pedigrees to test whether specific haplogroups and their defining SNPs confer risk of AD. We did not observe frequency differences between AD cases compared to controls overall or when stratified by sex. Therefore, we suggest that the genetic effect responsible for AD dementia in the affected Amish pedigrees is unlikely to be of mitochondrial origin and may be caused by nuclear genetic factors.     

Seasonal variation in conception and various pregnancy outcomes

Abstract

U.S. vital registration data on live births and data on abortions and ectopic pregnancies from a national hospital discharge survey were used to examine the seasonality of conceptions and the influence the conception pattern has on the monthly incidence of abortions and ectopic pregnancies. We found that in the United States conceptions follow a consistent seasonal pattern with the peak in November and December. However, when the pattern for conceptions is controlled, the monthly variation for abortions and ectopic pregnancies is not significant. Therefore, we find no monthly excess for any of these outcomes of pregnancy over that expected as a consequence of the seasonality of conception. We suggest the monthly variation for the number of each of these pregnancy outcomes will best be explained when the seasonal variation in conceptions is understood.     

Twin seasonality in a rural Catalonian population

The seasonality of twinning in the Spanish populations has not been studied until now. Differences between seasonal distribution of the twin conceptions and those of the single births have been observed in other populations. The aim of this work is to explore the frequency of twinning in a rural population from Catalonia during the nineteenth century, as well as the seasonality patterns characterizing each of the twinning types. Data corresponding to all births recorded at Tortosa (South Catalonia) from 1801 to 1900 have been analyzed in order to study the twinning distribution. The distribution of the moving averages of the monthly rates of twins shows a peak in autumn. Twinning distribution differs from the total births' distribution in Tortosa. This fact is very clear in the case of unlike-sexed twins that have their greater incidence in the last quarter of the year, while the total maternities have their peak in the first one.