The surprising implications of familial association in disease risk

Background: A wide range of diseases show some degree of clustering in families; family history is therefore an important aspect for clinicians when making risk predictions. Familial aggregation is often quantified in terms of a familial relative risk (FRR), and although at first glance this measure may seem simple and intuitive as an average risk prediction, its implications are not straightforward. Methods: We use two statistical models for the distribution of disease risk in a population: a dichotomous risk model that gives an intuitive understanding of the implication of a given FRR, and a continuous risk model that facilitates a more detailed computation of the inequalities in disease risk. Published estimates of FRRs are used to produce Lorenz curves and Gini indices that quantifies the inequalities in risk for a range of diseases. Results: We demonstrate that even a moderate familial association in disease risk implies a very large difference in risk between individuals in the population. We give examples of diseases for which this is likely to be true, and we further demonstrate the relationship between the point estimates of FRRs and the distribution of risk in the population. Conclusions: The variation in risk for several severe diseases may be larger than the variation in income in many countries. The implications of familial risk estimates should be recognized by epidemiologists and clinicians.Comment: 17 pages, 5 figure

Tyypin 2 diabeteksen ja siihen liittyvien ominaisuuksien periytyvyys

Disturbances in insulin sensitivity and insulin secretion precede the manifestation of type 2 diabetes. Both genes and environment contribute to the diabetes risk. Heritability indicates the proportion to which genotype determines the variability of a trait, such as for example blood glucose concentration. The current work was done for the Hjelt institute and for the Finnish institute of Molecular Medicine (FiMM) in the University of Helsinki. Heritability of insulin sensitivity, insulin secretion and traits associated with type 2 diabetes were estimated by means of twin and family studies. The twins belonged to the Finnish Twin Cohort Study of the University of Helsinki and the families participated in the Botnia study, a project on type 2 diabetes genetics. The collecting of the material was made between the years 1992 - 2004. Insulin sensitivity was measured by means of hyperinsulinaemic euglycaemic clamp technique. Insulin secretion was measured both via oral (OGTT) and intravenous (IVGTT) glucose tolerance tests. The heritability of body mass index (BMI) and type 2 diabetes were estimated in a follow-up study of twins. Furthermore, heritability estimates of several glucose metabolism and insulin sensitivity related traits were obtained by examining Botnia study families where at least two family members had type 2 diabetes. Altogether 66 monozygotic (MZ) and 85 dizygotic (DZ) twin pairs underwent OGTT. A subset of the pairs participated also in IVGTT- and clamp studies. The follow-up study was based on information that was received from 10400 twin pairs during a maximum of 28 years of follow-up. From the Botnia-study, 5810 adults from 942 families were chosen: 1707 of them had type 2 diabetes. The average family size was 6,17. On the basis of the metabolic studies, it was concluded that the genotype determines the insulin secretion's early phase, which begins immediately after the ingestion or infusion of glucose. The heritability of this trait varied between 55% and 76%. The majority of variation in insulin sensitivity, instead, seemed to be due to non-hereditary factors, as the heritability of insulin sensitivity was only 37%. In the follow-up study, 6.3% of male and 5.1% of female twins got type 2 diabetes. BMI calculated on the basis of the data recorded at the start of the follow-up, predicted future diabetes well. On average, the hazard ratio for type 2 diabetes was 1,22 per each BMI unit and the risk began to increase already from the BMI-value of 20kg/m2. The hazard ratios for type 2 diabetes in normal weight, overweight, obese and morbidly obese twins were 0.59, 2.96, 6.80 and 13.64, respectively. When BMI and type 2 diabetes were modelled together, the heritability of BMI in men was 75%, and 71% in women. Correspondingly, the heritability of type 2 diabetes was 73% in men and 64% in women, respectively. The genetic factors influencing BMI explained only 16% of the risk for type 2 diabetes among men and 21% of the risk among women. In the Botnia study, the highest heritability estimate for type 2 diabetes, 69%, was observed among individuals aged 35 to 60 years. The heritability of the early phase of insulin secretion varied between 41% (all subjects) and 50% (non-diabetic subjects). The heritability of insulin sensitivity was the same as among twins, from 37% to 40%. Among diabetes-related traits, the highest heritability estimates were obtained for lean body mass (53% to 65%), serum HDL cholesterol concentration (52% to 61%) and suppression of free fatty acids during OGTT (63% to 76%). The variation of all insulin sensitivity and insulin secretion -related traits were smaller within than between families. It is stated as a summary of this doctoral thesis that the risk for type 2 diabetes seems to be an inherited trait. A relatively small share in this risk, on the other hand, seems to be due to genes which influence BMI. Finally, the early phase of the pancreatic insulin secretion appears to be an aspect of metabolism that encompasses promising phenotypes for genomic studies.Häiriöt sokeriaineenvaihdunnan insuliiniherkkyydessä ja insuliininerityksessä edeltävät tyypin 2 diabeteksen puhkeamista. Sekä perimä (geneettiset tekijät) että elintavat vaikuttavat diabetesriskiin. Periytyvyys eli heritabiliteetti ilmaisee, paljonko perimä määrää mitattavan ominaisuuden kuten esimerkiksi verensokerin vaihtelua. Helsingin yliopiston lääketieteellisen tiedekunnan alaisessa, Hjelt-instituutille ja Suomen molekyylilääketieteen instituutille (FiMM) tehdyssä väitöstutkimuksessa selvitettiin sokeriaineenaihdunnan, insuliininerityksen ja diabetesriskin periytyvyyttä kaksos- ja perhetutkimuksen keinoin. Kaksoset kuuluivat Helsingin yliopiston Kaksostutkimukseen, joka vuonna 2014 täyttää 40 vuotta. Perheaineisto koottiin suomalaisesta Botnia-tutkimuksesta, joka on maailman huomattavimpia tyypin 2 diabeteksen perimää selvittäviä projekteja. Aineiston kokoaminen ja seuranta tehtiin vuosien 1992 - 2004 aikana. Tutkimuksessa määritettiin insuliiniherkkyys clamp-tekniikan avulla: tutkittavan henkilön veren insuliinitaso nostettiin keinotekoisesti halutulle tasolle ja katsottiin, kuinka paljon sokeriliuosta on annettava laskimoon estämään insuliinin aikaansaama verensokerin lasku. Insuliinineritys mitattiin sekä tavallista (oraalista, OGTT) että laskimonsisäistä (IVGTT) sokerirasitusta käyttäen. Tyypin 2 diabeteksen ja kehon painoindeksin (BMI) periytyvyys selvitettiin pitkässä seurantatutkimuksessa. Lisäksi useille sokeriaineenvaihduntaan ja insuliiniherkkyyteen liittyville piirteille määritettiin periytyvyys tutkimalla Botnia-tutkimukseen osallistuneita perheitä, joissa vähintään kahdella perheenjäsenellä on tyypin 2 diabetes. Kaikkian 66 identtiselle ja 85 epäidenttiselle kaksosparille tehtiin OGTT ja osalle lisäksi sekä IVGTT että clamp. Seurantatutkimus perustui 10400 kaksosparista saatuihin tietoihin. Pisin seuranta-aika oli 28 vuotta. Botnia-tutkimuksesta valittiin 942 perhettä, joihin kuului 5810 aikuista. Heistä 1707:llä oli tyypin 2 diabetes. Keskimääräinen perhekoko oli 6,17. Kaksosille tehtyjen aineenvaihduntatutkimusten perusteella ilmeni, että perimä määrää vahvasti erityisesti insuliininerityksen varhaista vaihetta, joka alkaa välittömästi sokerin nauttimisen tai laskimoon annostelun jälkeen. Tämän ominaisuuden periytyvyys vaihteli 55 ja 76% välillä. Valtaosa insuliiniherkkyyden vaihtelusta sen sijaan näytti johtuvan ei-perinnöllisistä syistä ja insuliiniherkkyyden periytyvyydeksi saatiin vain 37%. Seurantatutkimuksessa 6,3% mies- ja 5,1% naiskaksosista sairastui tyypin 2 diabetekseen. Seurannan alussa kerättyjen tietojen perusteella laskettu painoindeksi ennusti tulevaa diabetesta erittäin hyvin. Keskimäärin riskisuhde oli 1,22 jokaista nousevaa BMI-yksikköä kohti. Diabetesriski alkoi lisääntyä jo BMI-arvosta 20 kg/m2 lähtien. Normaalipainoisten, ylipainoisten, lihavien ja sairaalloisen lihavien riskisuhteet olivat 0,59, 2,96, 6,80 ja 13,64. Kun sekä BMI että tyypin 2 diabetes huomioitiin yhtä aikaa, saatiin BMI:n periytyvyydeksi 75% miehillä ja 71% naisilla. Vastaavasti tyypin 2 diabeteksen periytyvyydeksi saatiin miehillä 73% ja naisilla 64%. Painoindeksin perintötekijät selittivät vain 16% miesten ja 21% naisten riskistä sairastua tyypin 2 diabetekseen. Botniatutkimuksessa tyypin 2 diabeteksen periytyvyys oli suurimmillaan 69 prosenttia, 35 - 60 -vuotiaiden keskuudessa. Insuliininerityksen varhaisen vaiheen periytyvyys vaihteli 41% (kaikki tutkittavat) ja 50% (tutkittavat, joilla ei diabetesta) välillä. Insuliiniherkkyyden periytyvyys oli sama kuin kaksostutkimuksessa, 37-40%. Diabetekseen liittyvistä aineenvaihdunnan ominaisuuksista korkein periytyvyys saatiin kehon rasvattomalle massalle (53-65%), seerumin HDL-kolesteroli-pitoisuudelle (52-61%) ja OGTT:n aikaiselle vapaiden rasvahappojen pitoisuuden laskulle (63-76%). Kaikkien insuliiniherkkyyteen ja insuliinineritykseen liittyvien ominaisuuksien vaihtelu perheiden sisällä oli pienempää kuin perheiden välillä. Väitöstutkimuksen yhteenvetona todetaan, että riski sairastua tyypin 2 diabetekseen on periytyvä. Painoindeksiin vaikuttavilla geeneillä on merkittävä, kenties tähän asti oletettua pienempi osuus tässä riskissä. Lisäksi todetaan, että insuliininerityksen varhainen vaihe kannattaa huomioida haettaessa tyypin 2 diabetekselle altistavia perintötekijöitä esimerkiksi koko genomin laajuisissa assosiaatiotutukimuksissa

Selection for partial resistance to crown rust in oat

Crown rust, caused by the fungal pathogen, Puccinia coronata, severely reduces kernel quality and grain yield in oat. Partial resistance is considered to be a durable form of rust resistance. The objectives of this study were to evaluate the effectiveness of index selection as a method for improving partial resistance to crown rust, grain yield and seed weight in oat population, and to estimate heritabilities for area under disease progress curve (AUDPC) and genetic correlations between AUDPC and agronomic traits in both crown rust-inoculated and fungicide-treated plots. A single cycle of selection for partial resistance to crown rust was performed. The initial (CO) and selected (Cl) generations of two oat populations were evaluated in a field experiment in 2001 and 2002 at two Iowa locations. The selection, via a selection index, increased the levels of crown rust resistance and grain yield and seed weight in crown rust-inoculated plots, and seed weight in fungicide-treated plots. However, there was no significant change for the grain yield in the disease-free environment. In both CO and Cl population, AUDPC were highly heritable, and were favorably correlated with grain yield, seed weight and test weight measured in crown rust-treated plots. Realized heritabilities for all traits but grain yield under the disease-free environment were relatively high. Our results suggested that the index selection as a method for selecting oat lines with high levels of crown rust resistance, grain yield and seed weight is possible

“Development of Genetic and Genomic Predictors of Fertility in Argentinean Holstein Cattle.”

The overall aim of the studies described herein was to evaluate genetic variation in cattle fertility traits for development of genetic and genomic predictors in breeding strategies. Results from these experiments suggest that improvements in fertility through genetic selection are a possible approach to increase reproductive efficiency. Experiment 1 evaluated the development of genetic parameters associated with multiple ovulation and embryo transfer schemes in an attempt to assist producers in identifying animals with greater genetic merit for these protocols. This study confirmed that genetic selection of donors or sires appears to be a potential approach to improve efficiency of MOET procedures. Although low heritability would slow the progress, results shown in this work suggest that genetic improvement in fertility by selection for embryo transfer traits is possible. Experiment 2 evaluated fertility traits in Argentinean Holstein cattle in order to develop fertility genetic predictors for utilization in breeding strategies. The dollar fertility index ($F) included age to first calving (AFC) as a measure of initial reproductive performance and calving interval (CI) as an indicator of conception rate and success of early insemination. Values for$F ranged from -$76.6 to$139.4 in the current Holstein population. Results indicated substantial variation in fertility traits, suggesting that genetic selection would be highly effective in improving fertility

Combining Experimental Evolution and Genomics to Understand How Seed Beetles Adapt to a Marginal Host Plant

Genes that affect adaptive traits have been identified, but our knowledge of the genetic basis of adaptation in a more general sense (across multiple traits) remains limited. We combined population-genomic analyses of evolve-and-resequence experiments, genome-wide association mapping of performance traits, and analyses of gene expression to fill this knowledge gap and shed light on the genomics of adaptation to a marginal host (lentil) by the seed beetle Callosobruchus maculatus. Using population-genomic approaches, we detected modest parallelism in allele frequency change across replicate lines during adaptation to lentil. Mapping populations derived from each lentil-adapted line revealed a polygenic basis for two host-specific performance traits (weight and development time), which had low to modest heritabilities. We found less evidence of parallelism in genotype-phenotype associations across these lines than in allele frequency changes during the experiments. Differential gene expression caused by differences in recent evolutionary history exceeded that caused by immediate rearing host. Together, the three genomic datasets suggest that genes affecting traits other than weight and development time are likely to be the main causes of parallel evolution and that detoxification genes (especially cytochrome P450s and beta-glucosidase) could be especially important for colonization of lentil by C. maculatus

Genetic and genomic studies on milk production and composition, and longevity in New Zealand dairy goats : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Animal Science at Massey University, Manawatu, New Zealand

The New Zealand dairy goat industry is important for producing and exporting high-quality specialised dairy products aimed at niche markets. Efforts to increase the quantity and composition of goat milk will improve profits for farmers and deliver significant economic benefits to New Zealand. However, no formal program exists for the genetic improvement of dairy goats. Therefore, the general aim of this thesis was to perform genetic and genomic studies that contribute to the design of the breeding program for New Zealand dairy goats. The first studies estimated variance components and genetic parameters of total lactation yields of milk, fat and protein, somatic cell score and longevity. The main findings suggest sufficient variation and favourable genetic correlations between these traits, supporting their inclusion into a selection index that predicts profit per animal. A random regression test-day model was then used to predict lactation curves of milk, fat, protein and somatic cell score. Using this model for genetic evaluation will enable the dairy goat industry to move from total yields into the prediction of lactation curves, enabling more accurate predictions and the opportunity of selecting for extended lactations. The first genome-wide association study of dairy goats in New Zealand was conducted using 3,732 animals genotyped with the Caprine 50K SNP chip. A highly significant region on chromosome 19 was associated with yields of milk, fat and protein, and somatic cell score, and a region on chromosome 29 was associated with somatic cell score. A prototype single-step BayesC model was developed to predict genomic breeding values and demonstrated that including genomic information into the evaluation can increase the accuracy of predictions compared to the traditional methods based on pedigrees alone, which is currently implemented in the New Zealand dairy goat industry. This thesis demonstrates that a single-step prediction model that uses genomic information would put the New Zealand dairy goat industry in a very good position to implement a genomic selection scheme. Further studies are required to define clearer breeding objectives and to systematically design a breeding program for the genetic improvement of New Zealand dairy goats

From Structural Equation Models to Next-Generation Sequencing: The Evolving Landscape of Modern Behavioral Genetics

Boomsma, D.I. [Promotor]Dolan, C.V. [Promotor]Borsboom, D. [Copromotor