Multigenerational Pedigrees Research Articles

Effects ofBRCA1andBRCA2mutations on female fertility

Women with BRCA1/2 mutations have a significantly higher lifetime risk of developing breast or ovarian cancer. We suggest that female mutation carriers may have improved fitness owing to enhanced fertility relative to non-carriers. Here we show that women who are carriers of BRCA1/2 mutations living in natural fertility conditions have excess fertility as well as excess post-reproductive mortality in relation to controls. Individuals who tested positive for BRCA1/2 mutations who linked into multi-generational pedigrees within the Utah Population Database were used to identify putative obligate carriers. We find that women born before 1930 who are mutation carriers have significantly more children than controls and have excess post-reproductive mortality risks. They also have shorter birth intervals and end child-bearing later than controls. For contemporary women tested directly for BRCA1/2 mutations, an era when modern contraceptives are available, differences in fertility and mortality persist but are attenuated. Our findings suggest the need to re-examine the wider role played by BRCA1/2 mutations. Elevated fertility of female mutation carriers indicates that they are more fecund despite their elevated post-reproductive mortality risks.

Familial pulmonary fibrosis is the strongest risk factor for idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a lethal lung disorder of unknown etiology. The disease is likely the result of complex interactions between genetic and environmental factors. Evidence suggests that certain environmental factors, such as cigarette smoking and metal dust exposures, or comorbidities like gastroesophageal reflux, and type 2 diabetes mellitus (DM2) may increase risk to develop IPF. Substantial uncertainty remains, however, regarding these and other putative risk factors for IPF. In this study we performed a case-control analysis including 100 patients with IPF and 263 controls matched for age sex and place of residence. We used a structured questionnaire to identify potential risk factors for IPF, including environmental and occupational exposures as well as the relevance of family history of pulmonary fibrosis. The multivariate analysis revealed that family history of pulmonary fibrosis [OR = 6.1, CI95% 2.3-15.9; p < 0.0001] was strongly associated with increased risk of IPF. Actually, 20% of the cases reported a parent or sibling with pulmonary fibrosis. Gastroesophageal reflux [OR = 2.9, CI: 1.3-6.6; p = 0.007], former cigarette smoking [OR = 2.5, CI: 1.4-4.6, p = 0.003], and past or current occupational exposure to dusts, smokes, gases or chemicals [OR = 2.8, CI: 1.5-5.5; p = 0.002] were also associated with the disease. Despite being a significant risk factor on univariate analysis DM2 was not significant in multivariate analysis. These findings indicate that family history of pulmonary fibrosis is a strong risk factor for IPF. Also, we confirmed that occupational exposures, gastroesophageal reflux and former smoking increase the risk for this disease.

Is gastroschisis truly a sporadic defect? Familial cases of gastroschisis in Utah, 1997 to 2008

Gastroschisis remains an epidemiologic and pathogenetic dilemma, with genetics not thought to play a significant role in its etiology. The purpose of this study was to determine which gastroschisis cases in the Utah Birth Defect Network (UBDN) were related and the excess familial risk among multigenerational families. Gastroschisis cases born from 1997 through 2008 were identified from the statewide population-based UBDN and linked with the Utah Population Database (UPDB) to access multigenerational pedigrees. We analyzed these pedigrees using the familial standardized incidence ratio (FSIR). Of the 284 UBDN gastroschisis cases, one in 40 (n = 7; 2.5%) were reported to have another affected family member. Among these seven cases, three had affected sib pairs and four reported either a distant cousin, paternal uncle, maternal half-uncle, or paternal cousin with gastroschisis. UBDN-UPDB-linked cases resulted in many multigenerational pedigrees with the same affected descendents through marriage. We selected 30 pedigrees for repeated analysis based on two parameters: highest FSIRs with a p ≤ 0.01 and ≥2 cases. In these 30 pedigrees, FSIRs ranged from 3.7 to 93.5 (p < 0.009), each with two to eight distantly related cases (n = 64 distinct cases, representing 23% of the 284). We found a statistically significant excess risk for gastroschisis because of familial factors. Similar to many other birth defects, gastroschisis may fit a multifactorial model of inheritance. The UBDN-UPDB linkage provides a robust approach to investigating genetic factors. Genetic susceptibility should be further investigated because it may have a greater role in the etiology of gastroschisis than currently appreciated.

Potential cognitive endophenotypes in multigenerational families: segregating ADHD from a genetic isolate

Endophenotypes are neurobiological markers cosegregating and associated with illness. These biomarkers represent a promising strategy to dissect ADHD biological causes. This study was aimed at contrasting the genetics of neuropsychological tasks for intelligence, attention, memory, visual-motor skills, and executive function in children from multigenerational and extended pedigrees that cluster ADHD in a genetic isolate. In a sample of 288 children and adolescents, 194 (67.4%) ADHD affected and 94 (32.6%) unaffected, a battery of neuropsychological tests was utilized to assess the association between genetic transmission and the ADHD phenotype. We found significant differences between affected and unaffected children in the WISC block design, PIQ and FSIQ, continuous vigilance, and visual-motor skills, and these variables exhibited a significant heritability. Given the association between these neuropsychological variables and ADHD, and also the high genetic component underlying their transmission in the studied pedigrees, we suggest that these variables be considered as potential cognitive endophenotypes suitable as quantitative trait loci (QTLs) in future studies of linkage and association.

A quantitative genetic analysis of hibernation emergence date in a wild population of Columbian ground squirrels

The life history schedules of wild organisms have long attracted scientific interest, and, in light of ongoing climate change, an understanding of their genetic and environmental underpinnings is increasingly becoming of applied concern. We used a multi-generation pedigree and detailed phenotypic records, spanning 18 years, to estimate the quantitative genetic influences on the timing of hibernation emergence in a wild population of Columbian ground squirrels (Urocitellus columbianus). Emergence date was significantly heritable [h(2) = 0.22 ± 0.05 (in females) and 0.34 ± 0.14 (in males)], and there was a positive genetic correlation (r(G) = 0.76 ± 0.22) between male and female emergence dates. In adult females, the heritabilities of body mass at emergence and oestrous date were h(2) = 0.23 ± 0.09 and h(2) = 0.18 ± 0.12, respectively. The date of hibernation emergence has been hypothesized to have evolved so as to synchronize subsequent reproduction with upcoming peaks in vegetation abundance. In support of this hypothesis, although levels of phenotypic variance in emergence date were higher than oestrous date, there was a highly significant genetic correlation between the two (r(G) = 0.98 ± 0.01). Hibernation is a prominent feature in the annual cycle of many small mammals, but our understanding of its influences lags behind that for phenological traits in many other taxa. Our results provide the first insight into its quantitative genetic influences and thus help contribute to a more general understanding of its evolutionary significance.

Prevalence and ancestral origin of BRCA mutations in the Hispanic population: Insights for ancestry-informed genetic cancer risk assessment.

1514 Background: Little is known about prevalence or ancestral origins of BRCA1and BRCA2 (BRCA) mutations among high-risk Hispanics, the fastest growing relatively underserved population in the U.S. Methods: Individuals of self-reported Hispanic origin with a personal or family history of breast and/or ovarian cancer were enrolled in an IRB-approved registry and underwent genetic counseling and BRCA testing within a consortium of 14 high risk clinics across the U.S. Multigenerational pedigrees and data on grandparental geographic origins were obtained. Screening for recurrent BRCA mutations was done in three population-based cohorts. Haplotypes were constructed for recurrent mutations, and mutational age was estimated for a large BRCA1 rearrangement mutation (ex9-12del). Genotyping of 59 ancestry informative SNPs was performed and STRUCTURE analysis was used to determine ancestry admixture in BRCA carriers, with Los Angeles Mexican-American HapMap reference samples and an AmerIndian reference population seeded in the analyses. Results: Deleterious BRCA mutations were detected in 189/746 (25%) Hispanics (124 in BRCA1, 65 in BRCA2); 34 (5%) had one or more unclassified variants, and 523 (70%) had negative results. Mean age at diagnosis was 41 years for the 656 women with breast cancer. The most frequent mutations (n>5) were BRCA1 185delAG (n =18; occurring on the Jewish haplotype), ex9-12del (n=13), R71G (n=9), R1443X (n=6), and BRCA2 3492insT (n=10); accounting for 30% of all mutations. Large rearrangements (n=21) constituted 11% of all mutations. From mutational age analyses, BRCA1 ex9-12del was estimated to have arisen 74 generations (~1,480 years [920-2260]) ago; all carriers reported Mexican descent and admixture analyses suggested greater Amerindian ancestry than either the Mexican American reference panel or the Mexican 185delAG carriers who had more European ancestry. Conclusions: With a large sample of BRCA mutations among U.S. Hispanics from Mexico and Central America, our results suggest that ancestry-informed genetic screening for recurrent mutations (many of Spanish origin, as well as the Mexican BRCA1 ex9-12del founder mutation) could be cost effective.

Familial transmission of schizophrenia in Palau: A 20‐year genetic epidemiological study in three generations

Our genetic epidemiological studies of schizophrenia and other psychotic disorders (SCZ) in the isolated population of Palau have been ongoing for 20 years. Results from the first decade showed that Palau has an elevated prevalence of SCZ and that cases cluster in extended multigenerational pedigrees interconnected via complex genetic relationships after centuries of endogamous, but not consanguineous, marriages. The aim of our second decade of research, which extended data collection into a third generation of young, high-risk (HR) Palauans, was to identify significant predictors of intergenerational transmission of illness. Our findings revealed that degree of familial loading and gender effects on reproductive fitness are important modifiers of risk for transmission of SCZ. Among 45 distinct multiplex families, we identified 10 high-density (HD) Palauan families, each with 7-29 SCZ cases, which contain half of Palau's 260 SCZ cases and 80% of the 113 SCZ cases with one or more affected first-degree relatives, indicating that familial loading is a major risk factor for SCZ in Palau. Cases that belong to multiply affected sibships are more common than cases with an affected parent. Furthermore, only 6/38 multiply affected sibships have an affected parent, strong evidence that many unaffected parents are obligate carriers of susceptibility genes. Although reproductive fitness is dramatically reduced in affected males, the 30% minority who do become fathers are twice as likely as affected mothers to transmit SCZ to an offspring. As they evolve, these HD families can help to elucidate the genetic mechanisms that predict intergenerational transmission of SCZ.

A Clinical Characterization of Familial Keloid Disease in Unique African Tribes Reveals Distinct Keloid Phenotypes

This study is a clinical characterization of keloid scars in an African population comprising three rural tribes with familial keloids. Site distribution, morphologic features, and other characteristics of the scars were studied to assess whether each tribe had a specific scar phenotype. Keloid scar clinics were set up at Soba Hospital in Khartoum, Sudan, for patient recruitment and management. In addition, familial keloid cases were recruited from rural tribal populations during field trips. A database including clinical and demographic data and digital photographs of all keloid cases was established. Statistical analysis was conducted using SPSS and SAS software. One hundred eleven individuals with keloid scarring (67 male subjects and 44 female subjects) were recruited. Patients were predominantly from three multigenerational pedigrees (total of 38 nuclear families) afflicted with keloid scars residing in different rural regions of Sudan. Two distinct morphologic phenotypes of keloid scarring were observed. The first phenotype has been designated "superficial spreading" (horizontal) keloid and the second has been designated "raised" (vertical) keloid. Clinically significant features and statistically measurable morphologic parameters were compared among these phenotypes (p = 0.001). Furthermore, linear claw-like extensions of keloid (transgression) were noted to be significantly higher in the superficial spreading keloid phenotype (p = 0.03). There is strong evidence of different phenotypes of keloid scarring. Two distinct phenotypes have been observed, described, and statistically verified. Each tribe demonstrated one particular phenotype, with two being superficial spreading and one being raised. Other significant clinical characteristics have been described. This is of significance in understanding both the clinical basis and the genetic basis of keloid scarring.

The heritability of multiple male mating in a promiscuous mammal.

The tendency of females to mate with multiple males is often explained by direct and indirect benefits that could outweigh the many potential costs of multiple mating. However, behaviour can only evolve in response to costs and benefits if there is sufficient genetic variation on which selection can act. We followed 108 mating chases of 85 North American red squirrels (Tamiasciurus hudsonicus) during 4 years, to measure each female's degree of multiple male mating (MMM), and used an animal model analysis of our multi-generational pedigree to provide what we believe is the first estimate of the heritability of MMM in the wild. Female red squirrels were highly polyandrous, mating with an average of 7.0 ± 0.2 males on their day of oestrus. Although we found evidence for moderate levels of additive genetic variation (CV(A) = 5.1), environmental variation was very high (CV(E) = 32.3), which resulted in a very low heritability estimate (h(2) < 0.01). So, while there is genetic variation in this trait, the large environmental variation suggests that any costs or benefits associated with differences among females in MMM are primarily owing to environmental and not genetic differences, which could constrain the evolutionary response to natural selection on this trait.

Genome-wide mapping and identification of new quantitative trait loci affecting meat production, meat quality, and carcass traits within a Duroc purebred population1

Most QTL detection studies in pigs have been carried out in experimental F(2) populations. However, segregation of a QTL must be confirmed within a purebred population for successful implementation of marker-assisted selection. Previously, QTL for meat quality and carcass traits were detected on SSC 7 in a Duroc purebred population. The objectives of the present study were to carry out a whole-genome QTL analysis (except for SSC 7) for meat production, meat quality, and carcass traits and to confirm the presence of segregating QTL in a Duroc purebred population. One thousand and four Duroc pigs were studied from base to seventh generation; the pigs comprised 1 closed population of a complex multigenerational pedigree such that all individuals were related. The pigs were evaluated for 6 growth traits, 7 body size traits, 8 carcass traits, 2 physiological traits, and 11 meat quality traits, and the number of pigs with phenotypes ranged from 421 to 953. A total of 119 markers were genotyped and then used for QTL analysis. We utilized a pedigree-based, multipoint variance components approach to test for linkage between QTL and the phenotypic values using a maximum likelihood method; the logarithm of odds score and QTL genotypic heritability were estimated. A total of 42 QTL with suggestive linkages and 3 QTL with significant linkages for 26 traits were detected. These included selection traits such as daily BW gain, backfat thickness, loin eye muscle area, and intramuscular fat content as well as correlated traits such as body size and meat quality traits. The present study disclosed QTL affecting growth, body size, and carcass, physiological, and meat quality traits in a Duroc purebred population.

Quantitative Trait Locus (QTL) Linkage Analysis of a Large Pedigree with Von Willebrand Disease Identifies Novel Modifier Loci of Von Willebrand Factor Levels and Confirms Some Previously Reported Modifier Loci

AbstractAbstract 240Von Willebrand disease (VWD) is the most common inherited bleeding disorder with a prevalence ranging from 0.8 to 1.3%. VWD is characterized by incomplete penetrance and variable expressivity, even in families with a unifying VWF mutation, suggesting the presence of modifier genes. We diagnosed and characterized a 1500-member multigenerational Amish family in which 132 individuals exhibit a single autosomal-dominant C4120T mutation (R1374C) in the A1 domain of the mature von Willebrand Factor (VWF) molecule. When accounting for the C4120T mutation, analyses of coagulation factor VIII levels (FVIII:C) and log transformed, sex- and age-adjusted VWF levels in SOLAR estimated a heritability (h2) of 0.301 for VWF antigen levels (VWF:Ag; p=2.7×10−6), 0.386 for VWF ristocetin cofactor activity (VWF:RCo; p=1.16×10−8), and 0.280 for FVIII:C (p=1.52×10−5). These results demonstrate strong evidence of residual heritability of the traits despite the obvious effect of the 4120 mutation. Among individuals with the wild-type VWF CC4120 genotype, ABO genotype, the only known major modifier of VWF levels, explained 6.5, 10.0 and 4.2% of the variability in VWF:Ag, VWF:RCo and FVIII:C levels, respectively, suggesting that a significant genetic component of the variability of these traits remains unaccounted for.In order to search for modifier loci that contribute to the observed variability we then performed a primary genetic screen at an average 10 cM interval using a standard short tandem repeat polymorphism mapping set in a 384-member subset of the pedigree. Quantitative trait locus (QTL) linkage analysis was performed using SOLAR for VWF:Ag, VWF:RCo and FVIII:C. The highest LOD score generated demonstrated linkage of VWF:RCo to region 12p13 where VWF has been physically mapped (LOD=64.73). When accounting for the C4120T mutation, five other chromosomal regions were identified with LOD scores above 2.0 with linkage to FVIII:C, VWF:Ag, and/or VWF:RCo: 2q14 (LOD=2.48), 6p12 (LOD=2.22), 9q33 (LOD=2.84), 10q26 (LOD=2.29), and 16q11 (LOD=2.66). Notably, the ABO locus maps to chromosome 9q33, demonstrating by linkage the known effect of ABO on VWF levels.Five chromosomal regions demonstrated LOD scores between 1.5 and 2.0 for the above phenotypes: 3p14 (LOD=1.56), 4q34 (LOD=1.64), 5q33 (LOD=1.8373), 15q14 (LOD=1.78), and 21q21 (LOD=1.85). Comparison to other linkage and association studies such as the Genetic Analysis of Inherited Thrombophilia (GAIT) and the Framingham Study identified several concurrent peaks in our analysis. Specifically, 22q11and 9q34 were reported in the GAIT study as chromosomal regions linked to VWF:Ag and 6p22 was reported in the Framingham study as well as in the GAIT study as linked to the same phenotype. Furthermore the 22q11 and 21q21 signals display orthology to Mvwf6, a murine modifier region of VWF levels recently reported. Two other signals, 5q33 and 6p12 also display orthology with regions closely syntenic to Mvwf4, another murine modifier. These comparisons strengthen the validity of this multigenerational pedigree as a tool to identify genetic modifiers of the phenotypic variability of VWF levels and provide the basis to which chromosomal regions will be followed-up to identify causative alleles. While genome-wide association studies (GWAS) are characterized by the identification of common variants of relatively modest effect, linkage studies such as the one we present here may have the ability to identify rare variants as well as allelic heterogeneity at a given modifier locus, which may explain a significant portion of the observed variability and likely account for a portion of the genetic component not identified by GWAS analyses. Disclosures:No relevant conflicts of interest to declare.

Hidradenitis suppurativa (or Acne inversa) with autosomal dominant inheritance is not linked to chromosome 1p21.1‐1q25.3 region

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition characterized by swollen, painful, inflamed lesions in the axillae, groin, armpits and other parts of the body that contain apocrine glands. The aetiology of HS is unknown, and earlier reports indicate genetic locus responsible for this phenotype on chromosome 1p21.1-1q25.3, but no causative gene(s) have yet been identified. We studied two large multigeneration pedigrees (UR251 and UR252), in which the condition appeared to segregate as an autosomal dominant trait with 100% penetrance. No skipping of generations was observed in either family. Pedigrees consist of 96 individuals, including 25 affected individuals. Because of squamous cell carcinoma, a few deaths were reported in family UR0251. The locus on chromosome 1p21.1-1p25.3, known from previous studies is associated with HS, was excluded in both families by linkage and haplotype analyses. Further studies are in progress to identify the region that is associated with the phenotype in these families.

Amygdalar and hippocampal substrates of anxious temperament differ in their heritability

Anxious temperament (AT) in human and non-human primates is a trait-like phenotype evident early in life that is characterized by increased behavioural and physiological reactivity to mildly threatening stimuli 1–4. Studies in children demonstrate that AT is an important risk factor for the later development of anxiety disorders, depression, and comorbid substance abuse 5. Despite its importance as an early predictor of psychopathology, little is known about the factors that predispose vulnerable children to develop AT and the brain systems that underlie its expression. To characterize the neural circuitry associated with AT and the extent to which the function of this circuit is heritable, we performed a study in a large sample of rhesus monkeys phenotyped for AT. Using 238 young monkeys from a multigenerational single-family pedigree, we simultaneously assessed brain metabolic activity and AT while monkeys were exposed to the relevant ethological condition that elicits the phenotype. High-resolution 18F-deoxyglucose positron emission tomography (FDG-PET) was selected as the imaging modality since it provides semi-quantitative indices of absolute glucose metabolic rate, allows for simultaneous measurement of behaviour and brain activity, and has a time course suited to assess temperament-associated sustained brain responses. Results demonstrated that the central nucleus region of amygdala and the anterior hippocampus are key components of the neural circuit predictive of AT. Quantitative genetic analysis demonstrated significant heritability of the AT phenotype. Additionally, a voxelwise analysis revealed significant heritability of metabolic activity in AT-associated hippocampal regions. However, activity in the amygdala region predictive of AT was not significantly heritable. Furthermore, the heritabilities of the hippocampal and amygdala regions significantly differed from each other. Even though these structures are closely linked, the results suggest differential influences of genes and environment on how these brain regions mediate AT and the ongoing risk to develop anxiety and depression.

Association analysis of 33 lipoprotein candidate genes in multi-generational families of African ancestry

African ancestry individuals have a more favorable lipoprotein profile than Caucasians, although the mechanisms for these differences remain unclear. We measured fasting serum lipoproteins and genotyped 768 tagging or potentially functional single nucleotide polymorphisms (SNPs) across 33 candidate gene regions in 401 Afro-Caribbeans older than 18 years belonging to 7 multi-generational pedigrees (mean family size 51, range 21-113, 3,426 relative pairs). All lipoproteins were significantly heritable (P<0.05). Gender-specific analysis showed that heritability for triglycerides was much higher (P<0.01) in women than in men (women, 0.62+/-0.18, P<0.01; men, 0.13+/-0.17, P>0.10), but the heritability for LDL cholesterol (LDL-C) was higher (P<0.05) in men than in women (men, 0.79+/-0.21, P<0.01; women, 0.39+/-0.12, P<0.01). The top 14 SNPs that passed the false discovery rate threshold in the families were then tested for replication in an independent population-based sample of 1,750 Afro-Caribbean men aged 40+ years. Our results revealed significant associations for three SNPs in two genes (rs5929 and rs6511720 in LDLR and rs7517090 in PCSK9) and LDL-C in both the family study and in the replication study. Our findings suggest that LDLR and PCSK9 variants may contribute to a variation in LDL-C among African ancestry individuals. Future sequencing and functional studies of these loci may advance our understanding of genetic factors contributing to LDL-C in African ancestry populations.

A Major Gene Controls Leprosy Susceptibility in a Hyperendemic Isolated Population from North of Brazil

Leprosy is a chronic infectious disease that affects 250,000 new individuals/year worldwide. Genetic analysis has been successfully applied to the identification of host genetic factors affecting susceptibility to leprosy; however, a consensus regarding its mode of inheritance is yet to be achieved. We conducted a complex segregation analysis (CSA) on leprosy using data from the Prata Colony, an isolated, highly endemic former leprosy community located at the outskirts of the Brazilian Amazon. The colony offers large multiplex, multigenerational pedigrees composed mainly by descendents of a small number of original leprosy-affected families. Our enrollment strategy was complete ascertainment leading to the inclusion of the whole colony (2005 individuals, 225 of whom were affected) distributed in 112 pedigrees. CSA was performed using REGRESS software. CSA identified a best-fit codominant model, with a major gene accounting for the entire familial effect observed. The frequency of predisposing allele was estimated at 0.22. Penetrance for homozygous individuals for the predisposing allele >30 years old ranged from 56% to 85%, depending on sex. A strong major gene effect in the isolated, hyperendemic Prata Colony indicates enrichment of genetic risk factors, suggesting a population particularly suitable for leprosy gene identification studies.

PRNP allelic series from 19 years of prion protein gene sequencing at the MRC Prion Unit

Mutation of the human prion protein gene (PRNP) open reading frame (ORF) accounts for almost all reported familial concurrence of prion disease. The more common mutations globally: octapeptide repeat insertions, P102L, D178N, E200K, and V210I have occurred in large multigenerational pedigrees and display autosomal dominant inheritance, however, many rare genetic changes have been reported that are of uncertain pathogenicity. Based on 19 years of PRNP sequencing at the MRC Prion Unit, London, and analysis of 3664 samples from patients referred with suspected prion disease and healthy populations, we present novel allele combinations, healthy control population data, results of screening the PRNP ORF in DNA from the entire referral series and the CEPH human genome diversity cell line panel. Of the 10 alleles detected in patients for which detailed cases histories are presented, 4 are unreported (G54S, D167N, V209M, Q212PP), two changes are thought to be pathogenic but have not been described in our regions (P105L from the UK, G114V from India and Turkey), and the remainder reported in healthy control populations or in trans to known pathogenic mutations suggesting non- or low pathogenicity (G54S, 1-OPRI, G142S, N171S, V209M, E219K). New genotype-phenotype correlations and population frequencies presented will help the diagnosis and genetic counselling of those with suspected inherited prion disease.

FAM-MDR: A Flexible Family-Based Multifactor Dimensionality Reduction Technique to Detect Epistasis Using Related Individuals

We propose a novel multifactor dimensionality reduction method for epistasis detection in small or extended pedigrees, FAM-MDR. It combines features of the Genome-wide Rapid Association using Mixed Model And Regression approach (GRAMMAR) with Model-Based MDR (MB-MDR). We focus on continuous traits, although the method is general and can be used for outcomes of any type, including binary and censored traits. When comparing FAM-MDR with Pedigree-based Generalized MDR (PGMDR), which is a generalization of Multifactor Dimensionality Reduction (MDR) to continuous traits and related individuals, FAM-MDR was found to outperform PGMDR in terms of power, in most of the considered simulated scenarios. Additional simulations revealed that PGMDR does not appropriately deal with multiple testing and consequently gives rise to overly optimistic results. FAM-MDR adequately deals with multiple testing in epistasis screens and is in contrast rather conservative, by construction. Furthermore, simulations show that correcting for lower order (main) effects is of utmost importance when claiming epistasis. As Type 2 Diabetes Mellitus (T2DM) is a complex phenotype likely influenced by gene-gene interactions, we applied FAM-MDR to examine data on glucose area-under-the-curve (GAUC), an endophenotype of T2DM for which multiple independent genetic associations have been observed, in the Amish Family Diabetes Study (AFDS). This application reveals that FAM-MDR makes more efficient use of the available data than PGMDR and can deal with multi-generational pedigrees more easily. In conclusion, we have validated FAM-MDR and compared it to PGMDR, the current state-of-the-art MDR method for family data, using both simulations and a practical dataset. FAM-MDR is found to outperform PGMDR in that it handles the multiple testing issue more correctly, has increased power, and efficiently uses all available information.

Gender-Dependent Penetrance of Small Heterodimer Partner (SHP) Gene Deficiency in Overweight/Obese Chinese Pedigrees

Mutations of the small heterodimer partner (SHP) gene have been associated with mild obesity in Japanese subjects. This study was designed to investigate whether there was a similar association in 772 Chinese adults. A total of 272 subjects were normal weight, 423 were overweight and 77 were obese. Four non-synonymous mutations (R34X, H53fsdel10, G171A, G189E) were identified in 10 out of the 500 overweight/obese subjects, but were not seen in the normal weight controls (prevalence 2.00% versus 0.00%, respectively). The relatives of proband carriers, including 25 carriers and 33 non-carriers from three generations, were also screened for 10 multigenerational non-consanguineous pedigrees. A gender-dependent penetrance effect was observed in the pedigrees. Furthermore, the frequency of SHP gene mutations was significantly higher in those with type 2 diabetes compared with the non-diabetics (61.5% versus 28.1%, respectively). These data provide evidence of a gender-dependent effect on penetrance for SHP deficiency and suggest that SHP mutations increase susceptibility to type 2 diabetes.

Molecular marker‐based pedigrees for animal conservation biologists

AbstractPedigrees, depicting the genealogical relationships between individuals in a population, are of fundamental importance to several research areas including conservation biology. For example, they are useful for estimating inbreeding, heritability, selection, studying kin selection and for measuring gene flow between populations. Pedigrees constructed from direct observations of reproduction are usually unavailable for wild populations. Therefore, pedigrees for these populations are usually estimated using molecular marker data. Despite their obvious importance, and the fact that pedigrees are conceptually well understood, the methods, and limitations of marker‐based pedigree inference are often less well understood. Here we introduce animal conservation biologists to molecular marker‐based pedigrees. We briefly describe the history of pedigree inference research, before explaining the underlying theory and basic mechanics of pedigree construction using standard methods. We explain the assumptions and limitations that accompany many of these methods, before going on to explain methods that relax several of these assumptions. Finally, we look to future and discuss some recent exciting advances such as the use of single‐nucleotide polymorphisms, inference of multigenerational pedigrees and incorporation of non‐genetic data such as field observations into the calculations. We also provide some guidelines on efficient marker selection in order to maximize accuracy and power. Throughout we use examples from the field of animal conservation and refer readers to appropriate software where possible. It is our hope that this review will help animal conservation biologists to understand, choose, and use the methods and tools of this fast‐moving field.

Colorectal adenomas and cancer link to chromosome 13q22.1-13q31.3 in a large family with excess colorectal cancer

Background Colorectal cancer is the fourth most common type of cancer and the second most common cause of cancer death. Approximately 5% of colon cancers arise in the presence of a clear hereditary cancer condition; however, current estimates suggest that an additional 15-25% of colorectal cancers arise on the basis of unknown inherited factors. Association studies report several low-penetrance genetic variants associated with colon cancer risk. Large families, whereby precise inheritance can be correlated with phenotype, offer another approach to identify moderately penetrant genes and to isolate responsible genetic loci and mutations. The aim of this study was to identify additional genetic factors responsible for colon cancer using large multigenerational pedigrees with excess colorectal cancer.