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PubMed2004

Genetic variation near the hepatocyte nuclear factor-4 alpha gene predicts susceptibility to type 2 diabetes.

The Finland-United States Investigation Of NIDDM Genetics (FUSION) study aims to identify genetic variants that predispose to type 2 diabetes by studying affected sibling pair families from Finland. Chromosome 20 showed our strongest initial evidence for linkage. It currently has a maximum logarithm of odds (LOD) score of 2.48 at 70 cM in a set of 495 families. In this study, we searched for diabetes susceptibility variant(s) at 20q13 by genotyping single nucleotide polymorphism (SNP) markers in case and control DNA pools. Of 291 SNPs successfully typed in a 7.5-Mb interval, the strongest association confirmed by individual genotyping was with SNP rs2144908, located 1.3 kb downstream of the primary beta-cell promoter P2 of hepatocyte nuclear factor-4 alpha (HNF4A). This SNP showed association with diabetes disease status (odds ratio [OR] 1.33, 95% CI 1.06-1.65, P = 0.011) and with several diabetes-related traits. Most of the evidence for linkage at 20q13 could be attributed to the families carrying the risk allele. We subsequently found nine additional associated SNPs spanning a 64-kb region, including the P2 and P1 promoters and exons 1-3. Our results and the independent observation of association of SNPs near the P2 promoter with diabetes in a separate study population of Ashkenazi Jewish origin suggests that variant(s) located near or within HNF4A increases susceptibility to type 2 diabetes.

Basic Helix-Loop-Helix Leucine Zipper Transcriptio↗
PubMed1984

Genetic variation of abdominal fat, body weight, and carcass weight in a female broiler line.

Pedigreed matings in a commercial purebred female broiler selection line produced 311 males and 341 females, which were slaughtered at 50 days of age. Coefficients of variation of abdominal fat weights were higher than live and carcass weights. The coefficient of variation was reduced when abdominal fat was regressed on live weight or when percentage of live or carcass weight was used. Leaf fat was approximately two-thirds and gizzard fat was approximately one-third of the total abdominal fat. Heritabilities for abdominal fat were high, and the genetic correlations between the fat and live or carcass weights ranged from .43 to .50 in males and .32 to .40 in females. The phenotypic correlations between fat and live weight were reduced when abdominal fat weight was subtracted from live weight, showing that the part-whole relationship between abdominal fat included in live body weight increased the correlations. The heritabilities indicate that it should be possible to reduce abdominal fat by selection, and the genetic correlations signify that a method has to be devised to increase body weight while simultaneously reducing abdominal fat weight.

Abdomen↗
PubMed2004

Impact of genetic variation in interleukin-1 receptor antagonist and melanocortin-1 receptor genes on vulvar vestibulitis syndrome.

OBJECTIVE: To investigate the risk of vulvar vestibulitis syndrome (VVS) in the presence of specific genetic variants (polymorphisms) that affect chronic inflammation, pain and skin color. STUDY DESIGN: For a retrospective, case-control study performed at a university-based ambulatory gynecologic service, 36 consecutive VVS cases and 69 consecutive pain-free controls were selected. Polymerase chain reaction products containing genetic variants of 2 genes, the interleukin-1 receptor antagonist (IL1RN) and melanocortin-1 receptor (MC1R), were analyzed by 2 independent techniques, gel electrophoresis and direct sequencing. RESULTS: VVS cases were significantly more likely to be homozygous (+/+) for allele 2 of IL1RN as compared to controls (OR=4.4, 95% CI 1.11-17.14, P=.032). VVS cases were more likely to carry at least 1 of 6 loss-of-function polymorphisms of the MC1R gene as compared to controls, overall (OR=3.5, 95% CI 1.45-8.37, P=.005) and adjusted for race (OR=2.6, 95% CI 1.06-6.51, P=.037). The combined presence of allele 2 (+/+) IL1RN and at least 1 of the 6 MC1R polymorphisms resulted in an additive risk for VVS (OR=8.5; additive risk for VVS (OR=8.5; P=.046). CONCLUSION: The risk of VVS is increased with proinflammatory genetic variants of IL1RN and MC1R, and combined genetic effects are associated with additive risk. This study supports a genetic contribution to VVS, suggests an increased risk of VVS in women withfair skin and indicates potential new treatment and primary prevention options.

Case-Control Studies↗
PubMed2004

Genetic variation and health; towards individualized medicine.

BACKGROUND: Pediatric endocrine diseases and their adult consequences depend on interactions of environmental exposure factors with the genetic makeup of the individual. Much has been learned over the past two decades about the genetic component in cases of monogenic (Mendelian) disorders due to drastic disruption of a single gene. The majority of children consulting a pediatric endocrinologist, however, suffer from conditions not attributable to a single gene. The nature and mechanisms of more subtle alterations at multiple different genes that are responsible for the genetic component of most human morbidity and mortality is now only beginning to be elucidated, largely thanks to the vast amount of information that is becoming available through the human genome effort. OVERVIEW: The purpose of this review is to describe 1. the nature of the information on health-related human variation that is coming our of the genome effort; 2. how this variation can affect biology; 3. which research approaches show promise in linking DNA variation to disease; 4. how this variation is organized in genomic blocks of linkage disequilibrium; and 5. how this knowledge may, in the future, allow clinicians to individualize management of a specific patient according to his/her genetic makeup.

Genetic Predisposition to Disease↗
PubMed2005

A functional genetic variation of the serotonin (5-HT) transporter affects 5-HT1A receptor binding in humans.

In humans, 5-HT1A receptors are implicated in anxiety and depressive disorders and their treatment. However, the physiological and genetic factors controlling 5-HT1A receptor expression are undetermined in health and disease. In this study, the influence of two genetic factors on 5-HT1A receptor expression in the living human brain was assessed using the 5-HT1A-selective positron emission tomography (PET) ligand [11C]WAY 100635. After the genotyping of 140 healthy volunteers to study population frequencies of known single nucleotide polymorphisms (SNPs) in the 5-HT1A receptor gene, the influence of the common SNP [(-1018) C>G] on 5-HT1A receptor expression was examined in a group of 35 healthy individuals scanned with [11C]WAY 100635. In the PET group, we also studied the influence of a common variable number tandem repeat polymorphism [short (S) and long (L) alleles] of the 5-HT transporter (5-HTT) gene on 5-HT1A receptor density. Whereas, the 5-HT1A receptor genotype did not show any significant effects on [11C]WAY 100635 binding, 5-HT1A receptor binding potential values were lower in all brain regions in subjects with 5-HTTLPR short (SS or SL) genotypes than those with long (LL) genotypes. Although the PET groups are necessarily a small sample size for a genetic association study, our results demonstrate for the first time that a functional polymorphism in the 5-HTT gene, but not the 5-HT1A receptor gene, affects 5-HT1A receptor availability in man. The results may offer a plausible physiological mechanism underlying the association between 5-HTTLPR genotype, behavioral traits, and mood states.

Adult↗
PubMedDate not supplied

Genetic variation in the east Midlands.

According to history, the population of the British Isles derives its genepool from a succession of invaders and immigrants. The settlement pattern of these invaders gave rise to a patchwork of genepools, shown in previous genetic surveys. Specimens from 1117 blood donors of regionally subdivided East Midlands (Derbyshire, Nottinghamshire and Leicestershire) were analysed for 18 conventional genetic systems (blood groups, serum proteins and red cell enzymes), according to place of residence. Significant differences exist among the five geographically defined sub-populations, and it is argued that these are derived from the historical settlement of continental European populations in the region, especially the Danes and the Vikings.

Analysis of Variance↗
PubMed2006

Marriage and genetic variation across the lifespan: not a steady relationship?

The prevalence of marriage varies across the lifespan, as does its importance to reproduction and the nurturance of children. We examined genetic and environmental influences on self-reported marriage at each decade from 20 through 70 years of age, using data collected for the Duke Dementia Study, a followed-up subset of the World War II Veteran Twin Registry. Genetic influences best fit a common factor model, supplemented by another, age-specific, genetic factor at age 30. Broad heritability increased from age 20 through 40, and then decreased to zero by ages 60 and 70. A longitudinal Cholesky model best described environmental influences on marriage across the lifespan. Shared environmental factors showed their greatest influence at age 20, no influence at 30 or 40 years, and then, reappeared with influence at 60 and 70. Variance due to error and unique environmental influences increased steadily to age 50 years and then declined slightly.

Emotions↗
PubMed2000

Temporal and spatial genetic variation in spawning grounds of European hake (Merluccius merluccius) in the Bay of Biscay.

Polymorphism at five microsatellite loci were screened to determine the genetic variability and the temporal stability of population structure in natural populations of European hake (Merluccius merluccius, L.) within the Bay of Biscay. In addition, the control region (900 bp) and two protein coding genes (ATPase, subunits 6 and 8, 842 bp and a partial sequence of the ND1, 800 bp) of the mitochondrial DNA (mtDNA) were sequenced from geographically distant populations from the extremes of the species range. One hundred individuals from either side of a supposed stock boundary within the bay were collected in autumn 1997. This sampling strategy was repeated during hake spawning seasons in late spring of 1998 and 1999. Low levels of population subdivision were found between putative populations within years. Similarly, low levels of differentiation were found between autumn 1997 northern samples and spring 1998 southern samples which were collected 7 months later on spawning grounds. These results are discussed in relation to ecological, behavioural and oceanographic information. Sampling effects, which may influence these results, are also discussed. Theta (theta) estimates were significantly different from zero in every other pairwise comparison between geographical areas (north and south of the Bay of Biscay) and between years within the same area (P<0.05). Hierarchical analysis of molecular variance (AMOVA) does not confirm the temporal persistence of population structure. These results are discussed in relation to variance in reproductive success, and temporal spawning patterns, which may exist within the bay. mtDNA variability was very low between geographically distant samples from Norway and the Mediterranean Sea with only 10 variable sites found in a total of 2542 bp of mtDNA, these differences being exclusively in the D-loop.

Animals↗
PubMed2006

DISC1-NDEL1/NUDEL protein interaction, an essential component for neurite outgrowth, is modulated by genetic variations of DISC1.

Disrupted-In-Schizophrenia-1 (DISC1) is a unique susceptibility gene for major mental conditions, because of the segregation of its genetic variant with hereditary psychosis in a Scottish pedigree. Genetic association studies reproducibly suggest involvement of DISC1 in both schizophrenia and bipolar disorder in several ethnic groups. The DISC1 protein is multifunctional, and a pool of DISC1 in the dynein motor complex is required for neurite outgrowth in PC12 cells as well as proper neuronal migration and dendritic arborization in the developing cerebral cortex in vivo. Here, we show that a specific interaction between DISC1 and nuclear distribution element-like (NDEL1/NUDEL) is required for neurite outgrowth in differentiating PC12 cells. Among several components of the dynein motor complex, DISC1 and NDEL1 are selectively upregulated during neurite outgrowth upon differentiation in PC12 cells. The NDEL1 binding site of DISC1 was narrowed down to a small portion of exon 13, corresponding to amino acids 802-835 of DISC1. We demonstrate that genetic variants of DISC1, proximal to the NDEL1 binding site, affect the interaction between DISC1 and NDEL1.

Animals↗