Large-scale plasma proteomics comparisons through genetics and disease associations.

High-throughput proteomics platforms measuring thousands of proteins in plasma combined with genomic and phenotypic information have the power to bridge the gap between the genome and diseases. Here we performed association studies of Olink Explore 3072 data generated by the UK Biobank Pharma Proteomics Project1 on plasma samples from more than 50,000 UK Biobank participants with phenotypic and genotypic data, stratifying on British or Irish, African and South Asian ancestries. We compared the results with those of a SomaScan v4 study on plasma from 36,000 Icelandic people2, for 1,514 of whom Olink data were also available. We found modest correlation between the two platforms. Although cis protein quantitative trait loci were detected for a similar absolute number of assays on the two platforms (2,101 on Olink versus 2,120 on SomaScan), the proportion of assays with such supporting evidence for assay performance was higher on the Olink platform (72% versus 43%). A considerable number of proteins had genomic associations that differed between the platforms. We provide examples where differences between platforms may influence conclusions drawn from the integration of protein levels with the study of diseases. We demonstrate how leveraging the diverse ancestries of participants in the UK Biobank helps to detect novel associations and refine genomic location. Our results show the value of the information provided by the two most commonly used high-throughput proteomics platforms and demonstrate the differences between them that at times provides useful complementarity.

Tuberculosis in medieval Iceland: evidence from Hofstaðir, Keldudalur and Skeljastaðir.

As part of a larger research project, 274 skeletons from three medieval Icelandic sites were evaluated for signs of infectious disease and 32 were found to have lesions at least consistent with a diagnosis of tuberculosis (TB): eight non-adults ranging in age from infancy to up to 17 years of age, and 24 adults. A higher proportion of individuals from Skeljastaðir and Keldudalur were affected than at Hofstaðir, an observation which may be compatible with Hofstaðir's higher status. A higher number of male skeletons overall (n. 17) than female skeletons (n. 8) exhibited pathological change. The sample is unique for its high numbers of well-preserved infants, and the appearance of TB in children is indicative of continual transmission in a community. The changes recorded in infant remains are marked by destruction and minimal periosteal new bone formation, while one adult skeleton exhibits the classic sign of Pott's disease. Other signs on the skeletons include evidence for past lymphadenitis and iliopsoas (cold) abscess. These cases indicate that TB was likely introduced to Iceland soon after the settlement period and became endemic in different regions from at least the late 10th - mid 13th centuries.

Is breastfeeding 'normal'? Using the right language for breastfeeding.

BACKGROUND: Accurate terms aid clarity in thinking and prevent confusion. In the infant feeding field 'normal' can be ambiguous as biologically normal may not equate with culturally normal in a given time or place. Similarly, the use of the term 'intervention' is appropriate if a recommended practice is not perceived as 'normal' to that culture. OBJECTIVE: This article explores the meaning of 'normal' in the context of infant feeding, since mothers may not perceive breastfeeding as 'normal' when this differs from the experience in communities in which it is considered unusual. METHODS: Historical and recent sources were used to explore the effect of culture and established practice on perceptions of what is 'normal'. DISCUSSION: Iceland and several regions of Europe are used as examples of long-term abandonment of breastfeeding during the late Medieval and Early Modern periods and the 19th century. Ireland, the United Kingdom and the United States are discussed in relation to fluctuations and declines in breastfeeding prevalence in the 20th and 21st centuries. The rôle of science and the rise of mother-support groups for breastfeeding, interventions to promote breastfeeding, and the possibility of cultural change, are also discussed. IMPLICATIONS FOR PRACTICE: Culture influences the perception of what is 'normal' and where a culture has abandoned breastfeeding, or where it is in decline, women are unlikely to view it as the normal way to feed an infant. A more appropriate use of language is recommended, describing breastfeeding as 'biologically normal' or 'physiologically normal', as it is not always, and has not always been, culturally normal. In this context initiatives to improve breastfeeding rates can correctly be termed 'interventions'.

A frameshift deletion in the sarcomere gene MYL4 causes early-onset familial atrial fibrillation.

AIMS: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in man, causing substantial morbidity and mortality with a major worldwide public health impact. It is increasingly recognized as a highly heritable condition. This study aimed to determine genetic risk factors for early-onset AF. METHODS AND RESULTS: We sequenced the whole genomes of 8453 Icelanders and imputed genotypes of the 25.5 million sequence variants we discovered into 1799 Icelanders with early-onset AF (diagnosed before 60 years of age) and 337 453 controls. Each sequence variant was tested for association based on multiplicative and recessive inheritance models. We discovered a rare frameshift deletion in the myosin MYL4 gene (c.234delC) that associates with early-onset AF under a recessive mode of inheritance (allelic frequency = 0.58%). We found eight homozygous carriers of the mutation, all of whom had early-onset AF. Six of the homozygotes were diagnosed by the age of 30 and the remaining two in their 50s. Three of the homozygotes had received pacemaker implantations due to sick sinus syndrome, three had suffered an ischemic stroke, and one suffered sudden cardiac death. CONCLUSIONS: Through a population approach we found a loss of function mutation in the myosin gene MYL4 that, in the homozygous state, is completely penetrant for early-onset AF. The finding may provide novel mechanistic insight into the pathophysiology of this complex arrhythmia.

Microvascular lesions in the brain and retina: The age, gene/environment susceptibility-Reykjavik study.

OBJECTIVE: To investigate whether the severity and location of cerebral white matter hyperintensities (WMHs) and brain infarcts are correlated with the signs of retinal microvascular abnormalities in the elderly. METHODS: The study included 4,176 men and women (mean age, 76 years) who participated in the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study. Digital retinal images of both dilated eyes were taken and evaluated for the presence of retinal focal arteriolar signs (focal arteriolar narrowing and arteriovenous nicking) and retinopathy lesions (retinal blot hemorrhages and microaneurysms). Brain magnetic resonance imaging scans were acquired and evaluated for the presence and distribution of cerebral infarcts and WMHs. Logistic and multinomial logistic models were constructed to estimate the association of retinal microvascular signs to brain lesions. RESULTS: Controlling for demographic and major cardiovascular risk factors, we found that retinal focal arteriolar signs, but not retinopathy lesions, were significantly associated with an increasing load of subcortical and periventricular WMHs. The strongest association was found between retinal arteriolar signs and a heavier WMH load, specifically in the subcortical frontal lobe, and periventricular frontal and parietal caps. There was a tendency toward bilateral retinal focal arteriolar narrowing being more strongly associated with the heavier load of subcortical WMHs. Arteriovenous nicking was significantly associated with subcortical infarcts. INTERPRETATION: In older adults, retinal focal arteriolar signs, but not retinopathy lesions, are correlated with the load of diffuse WMHs, particularly those located in the subcortical frontal lobe, and the periventricular frontal and parietal caps of the brain.

Comparing Norse animal husbandry practices: paleoethnobotanical analyses from Iceland and Greenland.

The popular view of the Norse settlement across the North Atlantic describes colonies with similar subsistence practices being established from the Faroe Islands in the west to L'Anse aux Meadows in the east. The importance of plant resources to the Norse animal husbandry strategies implemented by settlers upon arrival are not well established, nor are the changes these strategies underwent, eventually resulting in different cultural solutions to varying environmental and social factors. This paper compares archaeobotanical samples from two Icelandic archaeological sites, Svalbarð and Gjögur, and one Greenlandic site, Gården Under Sandet (GUS). Results of this comparison suggest that heathland shrubs were an important fodder resource for caprines in both Iceland and Greenland while apophytes ("weedy taxa") were part of the cattle fodder in Greenland. Further, the results indicate that mucking out of cattle barns to provide fertilizer was likely practiced at the GUS site in the Western Norse settlement of Greenland.

A new methodological approach to nonverbal behavior analysis in cultural perspective.

The measurement of human behavior is a complex task, both for psychologists and human sciences researchers and with respect to technology, since advanced and sophisticated instruments may have to be implemented to manage the plurality of variables involved. In this article, an observational study is presented in which a quantitative procedure, the external variables method (Duncan & Fiske, 1977), was integrated with a structural analysis (Magnusson, 1993, 2000) in order to detect the hidden organization of nonverbal behavior in Italian and Icelandic interactions. To this aim, Theme software was introduced and employed. The results showed that both the frequency and the typology of gestures deeply change as a function of culture. Moreover, a high number of patterns was detected in both Italian and Icelandic interactions: They appeared to be complex sequences in which a huge number of events were constantly happening and recurring. In this domain, Theme software provides a methodological progression from the quantitative to the structural approach.

Defining constant versus variable phenotypic features of women with polycystic ovary syndrome using different ethnic groups and populations.

CONTEXT: The phenotype of women with polycystic ovary syndrome (PCOS) is variable, depending on the ethnic background. OBJECTIVE: The phenotypes of women with PCOS in Iceland and Boston were compared. DESIGN: The study was observational with a parallel design. SETTING: Subjects were studied in an outpatient setting. PATIENTS: Women, aged 18-45 yr, with PCOS defined by hyperandrogenism and fewer than nine menses per year, were examined in Iceland (n = 105) and Boston (n = 262). INTERVENTION: PCOS subjects underwent a physical exam, fasting blood samples for androgens, gonadotropins, metabolic parameters, and a transvaginal ultrasound. MAIN OUTCOME MEASURES: The phenotype of women with PCOS was compared between Caucasian women in Iceland and Boston and among Caucasian, African-American, Hispanic, and Asian women in Boston. RESULTS: Androstenedione (4.0 +/- 1.3 vs. 3.5 +/- 1.2 ng/ml; P < 0.01) was higher and testosterone (54.0 +/- 25.7 vs. 66.2 +/- 35.6 ng/dl; P < 0.01), LH (23.1 +/- 15.8 vs. 27.6 +/- 16.2 IU/liter; P < 0.05), and Ferriman Gallwey score were lower (7.1 +/- 6.0 vs. 15.4 +/- 8.5; P < 0.001) in Caucasian Icelandic compared with Boston women with PCOS. There were no differences in fasting blood glucose, insulin, or homeostasis model assessment in body mass index-matched Caucasian subjects from Iceland or Boston or in different ethnic groups in Boston. Polycystic ovary morphology was demonstrated in 93-100% of women with PCOS in all ethnic groups. CONCLUSIONS: The data demonstrate differences in the reproductive features of PCOS without differences in glucose and insulin in body mass index-matched populations. These studies also suggest that measuring androstenedione is important for the documentation of hyperandrogenism in Icelandic women. Finally, polycystic ovary morphology by ultrasound is an almost universal finding in women with PCOS as defined by hyperandrogenism and irregular menses.

Association of phosphodiesterase 4D polymorphisms with ischemic stroke in a US population stratified by hypertension status.

BACKGROUND AND PURPOSE: Phosphodiesterase 4D (PDE4D) underlies the STRK1 linkage peak for stroke on chromosome 5q12 identified in Iceland. We tested association of 13 single-nucleotide polymorphisms (SNPs) and 1 microsatellite in a nested case-control sample of elderly white women (>65 years of age) from the Study of Osteoporotic Fractures (SOF) in the United States. METHODS: The genotypes of 248 women who experienced an incident ischemic stroke during an average of 5.4 years of follow-up were compared with 560 controls. RESULTS: Marginal associations with stroke (P<0.10) were found for 3 polymorphisms. Stratification of the population by hypertension markedly strengthened the association. SNPs 9 (hazard ratio [HR], 0.48; 95% CI, 0.26 to 0.91), 42 (HR, 1.73; 95% CI, 1.10 to 2.70), 219 (HR, 1.73; 95% CI, 1.13 to 2.64), and 220 (HR, 1.56; 95% CI, 1.05 to 2.32) showed significant association with stroke (P<0.05) under a dominant model in subjects without hypertension at baseline, and SNP 175 was significantly associated with stroke under an additive model (HR, 0.76; 95% CI, 0.59 to 0.98) in subjects with hypertension. Furthermore, the microsatellite AC008818-1 showed association with stroke only in the nonhypertensive subjects. Based on results in Iceland, specific haplotypes were tested in SOF, and stratification by hypertension also affected these association results. CONCLUSIONS: These data are consistent with an association of the PDE4D gene with stroke in a non-Icelandic sample and suggest an effect of hypertension status.

High level of male-biased Scandinavian admixture in Greenlandic Inuit shown by Y-chromosomal analysis.

We have used binary markers and microsatellites on the Y chromosome to analyse diversity in a sample of Greenlandic Inuit males. This sample contains Y chromosomes typical of those found in European populations. Because the Y chromosome has a unique and robust phylogeny of a time depth that precedes the split between European and Native American populations, it is possible to assign chromosomes in an admixed population to either continental source. On this basis, 58+/-6% of these Y chromosomes have been assigned to a European origin. The high proportion of European Y chromosomes contrasts with a complete absence of European mitochondrial DNA and indicates strongly male-biased European admixture into Inuit. Comparison of the European component of Inuit Y chromosomes with European population data suggests that they have their origins in Scandinavia. There are two potential source populations: Norse settlers from Iceland, who may have been assimilated 500 years ago, and the Danish-Norwegian colonists of the eighteenth century. Insufficient differentiation between modern Icelandic and Danish Y chromosomes means that a choice between these cannot be made on the basis of diversity analysis. However, the extreme sex bias in the admixture makes the later event more likely as the source.

Differences in prevalence of seasonal affective disorder that are not explained by either genetic or latitude differences.

The prevalence of winter SAD was measured in two groups of a(lult Manitobans of wholly Icelandic (lescent, 210 resident in Winnipeg (50 degrees N) and 252 resident in the nearby Interlake district (50.5 degrees N), using the Seasonal Pattern Assessment Questionnaire (SPAQ). These groups live practically at the same latitude and are according to all indications genetically identical. The age-and-sex-standardized prevalence rates of winter SAD proved to be markedly higher in the Winnipeg population than in the Interlake population: 4.8% and 1.2% (p<0.001), respectively. This four-fold dif ference is evidently unexplained by genetic factors or a difference in latitude; its causes have yet to be discovered.

Seasonal affective disorders: relevance of Icelandic and Icelandic-Canadian evidence to etiologic hypotheses.

OBJECTIVE: This study tests the suggestion of earlier studies concerning the importance of genetic factors in the etiology of winter seasonal affective disorders (SADs) and subsyndromal winter SAD (S-SAD). METHOD: Two study populations of Winnipeg, Manitoba residents were canvassed: 250 adults of wholly Icelandic descent and 1000 adults of non-Icelandic descent. We distributed the Seasonal Pattern Assessment Questionnaire by mail to these 2 populations, yielding 204 and 449 valid responses, respectively. RESULTS: Rates of SAD and S-SAD proved markedly lower in the Icelandic population than those in the non-Icelandic population. CONCLUSIONS: These differences seem unexplained by differences in ambient light or climate, thus indicating that genetic factors contribute to the expression of SADs. Compared with earlier findings from a group of adults of wholly Icelandic descent living in nearby rural Manitoba, the etiologic importance of as-yet-undetermined environmental factors unrelated to latitude or ambient light is also indicated.

[Icelandic genealogical registry sheds light on the significance of heredity in osteoarthritis]. / Isländskt släktregister ger kunskap om arvets betydelse vid artros.

Osteoarthritis is a heterogeneous and multifactorial disease with many pathogenic mechanisms implicated in its development and progression. Although osteoarthritis is a manifestation of certain metabolic, mechanical or inflammatory events, several distinct forms of osteoarthritis are inherited as dominantly acquired Mendelian traits. Gathering evidence is showing that inheritance and possible mutations in genes associated with osteoarthritis can play a major role in the common form of osteoarthritis in many joints. By the introduction of new biological methods for finding gene defects the search for possible gene defects have taken mainly three forms: (1) Parametric linkage analysis of rare families in which osteoarthritis segregates as a Mendelian trait; (2) model free linkage analysis of affected sibling pairs, and (3) association analysis of known candidate genes. Mutations today known to be associated with osteoarthritis all occur in relatively rare syndromes or diseases, which have osteoarthritis as a major component. In recent years many loci have been found associated with the "common osteoarthritis phenotype". Chromosomes 2, 4, 6, 11 and 16 were identified in multiple genome scans and are therefore the most likely to encode susceptibility. Ongoing studies will lead to classifications of the "common osteoarthritis" based on the exact causative gene defects, rather than on their variable clinical and radiographic phenotype. Hopefully, these studies will lead to future new therapy of osteoarthritis.

Distribution of the CCR5 gene 32-basepair deletion in West Europe. A hypothesis about the possible dispersion of the mutation by the Vikings in historical times.

The chemokine receptor CCR5 constitutes the major coreceptor for the macrophage-tropic strains of HIV-1. A mutant allele of the CCR5 gene named Delta32 was shown to provide to homozygotes a strong resistance against infection by HIV. The frequency of the Delta32 allele was collected in 7328 noninfected unrelated individuals from 31 different European populations, and in Cyprus, Turkey, Daghestan, and North-Africa. The Delta32 allele was found in all populations studied, with a mean frequency of about 8.0%. A north to south gradient correlating latitude with Delta32 allelic frequencies was found (r = 0.795, p < 10(-9)), with highest allele frequencies in Nordic countries. We hypothesized that the Delta32 allele was disseminated in Europe by the Vikings during the eighth to the tenth centuries, because the most elevated values of this variant are actually found in their actual populations, and because they raided during the corresponding period in most European countries.

Cardiac structure and exercise blood pressure in urban and rural Canadian men of Icelandic descent.

The objective of the study was to determine the relationship between exercise systolic blood pressure (ESBP), during bicycle ergometry, and echocardiographically determined left ventricular structure in rural and urban Canadian men of Icelandic descent. The study was cross-sectional in design. The settings were urban Winnipeg and the rural Interlake District in the province of Manitoba, Canada. Subjects were adult male volunteers from families of wholly Icelandic descent. The subjects were 30 to 60 years of age and had supine blood pressure < 160/95 mm Hg. Anthropomorphic measurements, echocardiography and sphygmomanometry, at rest and during bicycle ergometry, were performed on all subjects. Prevalence of exaggerated ESBP (> or = 200 mm Hg) and left ventricular hypertrophy (LVH) was not significantly different in the two groups. In all but one individual LVH was classified as eccentric hypertrophy. In both urban and rural subjects with exaggerated ESBP, left ventricular mass index (LVMI) was greater than in those subjects without exaggerated ESBP. The LVMI correlated with ESBP at the highest workloads (> or = 150 W). Multivariate analysis of all subjects showed that cardiac index, ESBP, body mass index, and low exercise heart rate were predictive of LVMI. There was no significant difference in prevalence of ESBP or LVH between urban and rural Manitobans of Icelandic descent. However, LVMI levels were lower, and values for ESBP greater, in the rural group compared with the urban group. Within each of the two groups there was a positive association between ESBP and LVMI; hence, the study supports findings of our previous investigation showing evidence of early target organ effects in normotensive men with an exaggerated ESBP.

Plasma fatty acids and lipids in two separate, but genetically comparable, Icelandic populations.

Levels of serum lipids and lipoproteins, and the fatty acid composition of plasma phospholipids, were measured in two genetically comparable, but widely separated, populations. The 1975 mortality rates for ischemic heart disease were significantly higher in one of these populations, the Manitoban residents of pure Icelandic descent, than in the other, a rural population from Northeastern Iceland. Two study populations, Icelanders and Icelandic-Canadians, were drawn from these larger populations. The study populations were matched for age and sex and divided into three age groups, 20-39, 40-59, and 60-69 years. In comparison to the Icelandic-Canadians, the Icelanders exhibited significantly higher levels of total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol, but lower triglyceride levels. Their plasma phospholipids contained significantly lower levels of saturated fatty acids (SFA), monounsaturated fatty acids, and n-6 polyunsaturated fatty acids (PUFA); but their n-3 PUFA levels were three times as high. It was additionally found that fatty acid composition of plasma phospholipids differed among Icelanders of different ages. SFA levels were significantly lower, and n-6 PUFA levels significantly higher, in the 20-39 year group than in the 60-69 year group, possibly due to different dietary fat consumption patterns between generations. No corresponding age-related difference in the fatty acid composition of plasma phospholipids was found in the Icelandic-Canadian study population. As the Icelandic and Icelandic-Canadian groups are assumed to be genetically similar, the biochemical differences between them are evidently due to environmental, probably dietary, differences. The findings indicate that n-3 PUFA may be cardioprotective in the context of an otherwise atherogenic diet.

The relationship of serum ferritin with sex and exercise in Canadians of Icelandic descent: implications for prevention of coronary artery disease.

OBJECTIVE: To investigate the relationship of serum ferritin with sex and exercise. DESIGN AND SETTING: A cross-sectional design study carried out in Winnipeg, Manitoba. SUBJECTS: Urban Canadians of Icelandic descent, aged 21 to 60 years, took part in this investigation. Subjects were stratified by age, sex and menstrual status. INTERVENTIONS: Venous blood samples from fasting subjects were drawn for serum ferritin, hemoglobin and hematocrit analyses. Various anthropomorphic measurements were taken, and subjects underwent submaximal cycle ergometry testing. A health and lifestyles questionnaire and a four-day prospective food record were administered. MAIN RESULTS: Mean serum ferritin levels obtained were 187.93 and 47.84 micrograms/L for males and females, respectively. Mean serum ferritin levels were 33.06 micrograms/L and 71.14 micrograms/L for premenopausal and postmenopausal females, respectively. The mean weekly consumption of alcohol was 190 mL/week and 80 mL/week for males and females, respectively. The mean dietary intake of iron was 27.3 and 18.9 mg/day for males and females, respectively. Males, but not females, who exercised 45 mins or more per week had significantly lower levels of serum ferritin than their sedentary counterparts. In males, hemoglobin, hematocrit and the consumption of alcohol were positively correlated with serum ferritin, while exercise time was negatively correlated with serum ferritin. A trend towards lower serum ferritin levels at higher workloads was observed in males, but did not reach statistical significance. In females, age and dietary intake of iron were found to be positively correlated with serum ferritin, while history of anemia, menstrual status and workload were negatively correlated with serum ferritin. CONCLUSIONS: These findings suggest that regular aerobic exercise may decrease iron stores in the body. This may be clinically significant since high serum ferritin has been cited as a risk factor for coronary artery disease.