Neutrophil-to-lymphocyte ratio (NLR) variations in relationship with childhood maltreatment in patients with anorexia nervosa: a retrospective cohort study.

PURPOSE: Anorexia nervosa (AN) is a serious mental illness. It is frequently accompanied by a history of childhood maltreatment (CM) that may constitute a specific ecophenotype in patients with eating disorders necessitating special assessment and management. This retrospective study tested whether in patients with AN, CM-related chronic stress may manifest through low-grade inflammation reflected by an increase in white blood cell ratios (neutrophil-to-lymphocyte ratio, NLR, platelet-to-lymphocyte ratio, and monocyte-to-lymphocyte ratio). METHODS: Participants (N = 206) were enrolled at an eating disorder daycare unit in Montpellier, France, from March 2013 and January 2020. CM was assessed using the childhood trauma questionnaire (CTQ). The Eating Disorder Examination Questionnaire (EDE-Q) and the MINI were used to assess AN severity and the other clinical characteristics, respectively. RESULTS: NLR was higher in patients with AN and history of CM (p = 0.029) and in patients with AN and history of emotional abuse (p = 0.021), compared with patients with AN without history of CM. In multivariate analysis, emotional abuse (ß = 0.17; p = 0.027) contributed significantly to NLR variability. CONCLUSION: In patients with AN, NLR is a low-grade inflammation marker that is influenced by various sociodemographic, clinical and biological factors. It is more directly affected by some CM types, especially emotional abuse, than by the presence/absence of CM history. Future studies should focus on mediators between CM and increased inflammation, such as interoceptive awareness, emotional dysregulation, food addiction, and stress sensitization. LEVEL OF EVIDENCE: III. Evidence obtained from well-designed cohort or case-control analytic studies.

Genetic contributors to variation in alcohol consumption vary by race/ethnicity in a large multi-ethnic genome-wide association study.

Alcohol consumption is a complex trait determined by both genetic and environmental factors, and is correlated with the risk of alcohol use disorders. Although a small number of genetic loci have been reported to be associated with variation in alcohol consumption, genetic factors are estimated to explain about half of the variance in alcohol consumption, suggesting that additional loci remain to be discovered. We conducted a genome-wide association study (GWAS) of alcohol consumption in the large Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort, in four race/ethnicity groups: non-Hispanic whites, Hispanic/Latinos, East Asians and African Americans. We examined two statistically independent phenotypes reflecting subjects' alcohol consumption during the past year, based on self-reported information: any alcohol intake (drinker/non-drinker status) and the regular quantity of drinks consumed per week (drinks/week) among drinkers. We assessed these two alcohol consumption phenotypes in each race/ethnicity group, and in a combined trans-ethnic meta-analysis comprising a total of 86 627 individuals. We observed the strongest association between the previously reported single nucleotide polymorphism (SNP) rs671 in ALDH2 and alcohol drinker status (odd ratio (OR)=0.40, P=2.28 × 10-72) in East Asians, and also an effect on drinks/week (beta=-0.17, P=5.42 × 10-4) in the same group. We also observed a genome-wide significant association in non-Hispanic whites between the previously reported SNP rs1229984 in ADH1B and both alcohol consumption phenotypes (OR=0.79, P=2.47 × 10-20 for drinker status and beta=-0.19, P=1.91 × 10-35 for drinks/week), which replicated in Hispanic/Latinos (OR=0.72, P=4.35 × 10-7 and beta=-0.21, P=2.58 × 10-6, respectively). Although prior studies reported effects of ADH1B and ALDH2 on lifetime measures, such as risk of alcohol dependence, our study adds further evidence of the effect of the same genes on a cross-sectional measure of average drinking. Our trans-ethnic meta-analysis confirmed recent findings implicating the KLB and GCKR loci in alcohol consumption, with strongest associations observed for rs7686419 (beta=-0.04, P=3.41 × 10-10 for drinks/week and OR=0.96, P=4.08 × 10-5 for drinker status), and rs4665985 (beta=0.04, P=2.26 × 10-8 for drinks/week and OR=1.04, P=5 × 10-4 for drinker status), respectively. Finally, we also obtained confirmatory results extending previous findings implicating AUTS2, SGOL1 and SERPINC1 genes in alcohol consumption traits in non-Hispanic whites.

Risk factors of suicide re-attempt: A two-year prospective study.

BACKGROUND: History of suicide attempt (SA) is the strongest predictor of a new SA and suicide. It is primordial to identify additional risk factors of suicide re-attempt. The aim of this study was to identify risk factors of suicide re-attempt in patients with recent SA followed for 2 years. METHODS: In this multicentric cohort of adult inpatients, the median of the index SA before inclusion was 10 days. Clinicians assessed a large panel of psychological dimensions using validated tools. Occurrence of a new SA or death by suicide during the follow-up was recorded. A cluster analysis was used to identify the dimensions that best characterized the population and a variable "number of personality traits" was created that included the three most representative traits: anxiety, anger, and anxious lability. Risk factors of re-attempt were assessed with adjusted Cox regression models. RESULTS: Among the 379 patients included, 100 (26.4 %) re-attempted suicide and 6 (1.6 %) died by suicide. The two major risk factors of suicide re-attempt were no history of violent SA and presenting two or three personality traits among trait anxiety, anger and anxious lability. LIMITATIONS: It was impossible to know if treatment change during follow-up occur before or after the re-attempt. DISCUSSION: One of the most important predictors of re-attempt in suicide attempters with mood disorders, was the presence of three personality traits (anger, anxiety, and anxious lability). Clinicians should provide close monitoring to patients presenting these traits and proposed treatments specifically targeting these dimensions, especially anxiety.

Linkage and association between insulin-dependent diabetes mellitus (IDDM) susceptibility and markers near the glucokinase gene on chromosome 7.

Insulin-dependent diabetes mellitus (IDDM) is characterized by autoimmune destruction of the insulin secreting beta-cells of the pancreas and subsequent disruption of glucose metabolism. The tendency of IDDM to cluster in families and the modest (36%) concordance rate in monozygotic twins indicates that both genetic and environmental factors contribute to IDDM susceptibility. Recent genome-wide searches using the affected sib-pair (ASP) approach have provided evidence for novel loci, in addition to HLA (IDDM1) and insulin (IDDM2), which show evidence of linkage to IDDM (P < 0.05). We have evaluated 35 microsatellite marker loci on human chromosome 7 for linkage to IDDM in 339 affected sib-pair families. Increased sharing of parental haplotypes in affected sib-pairs was detected for two microsatellite markers flanking glucokinase (GCK). Preferential transmission of alleles to affected offspring was observed at one of these marker loci, GCK3, indicating linkage disequilibrium between the marker and a disease susceptibility locus. This combination of linkage and disease association suggests that glucokinase, or a gene in the vicinity, plays an important part in IDDM susceptibility.

Diminished support for linkage between manic depressive illness and X-chromosome markers in three Israeli pedigrees.

The hypothesis that chromosomal region Xq27-28 harbours a gene for manic-depression has been a focus of interest in human genetics. X-linked inheritance of manic depressive illness has been re-examined in 3 multigeneration Israeli kindreds. Extension and re-evaluation of pedigree data, including new individuals, diagnostic follow-up, and analysis with DNA markers, shows greatly diminished support for linkage to Xq28. The peak lod scores in two of the pedigrees have dropped several lod units to clearly negative values at the RCP-F8-G6PD gene cluster. On the other hand, positive lod scores (Zmax = 2.09) are sustained in another pedigree at the same map location. None of the pedigrees show linkage to more proximal markers, including the Xq27 locus DXS98. Our analysis underscores the uncertainties in studying complex disorders.

Linkage mapping of dopa-responsive dystonia (DRD) to chromosome 14q.

Dopa-responsive dystonia (DRD) is an autosomal-dominant neurological disorder which appears to result from a genetically determined deficiency of striatal dopamine. Pathological evidence suggests that this may be due to the establishment of a reduced number of dopaminergic nerve terminals in the striatum, or to an excessive reduction (pruning) of these terminals in early development. We have mapped the DRD gene to chromosome 14 by linkage analysis in 3 families with a maximum 2-point lod score of 4.67 at 8.6 centiMorgans from D14S63; maximum multipoint lod scores > 6 were obtained for the intervals D14S47-D14S52 and D14S52-D14S63. The flanking loci D14S47 and D14S63 define a region of about 22 cM as containing the DRD gene.

Evaluation of a susceptibility gene for schizophrenia on chromosome 6p by multipoint affected sib-pair linkage analysis.

The influence of genetic factors in schizophrenia has been convincingly demonstrated by family, twin and adoption studies, but the mode of transmission remains uncertain. The reported pattern of recurrence risks suggests a set of interacting loci. Based on prior evidence for linkage on chromosome 6p (K. Kendler, pers. comm.), we have scanned the short arm of chromosome 6 in 54 families for loci predisposing to schizophrenia, using 25 microsatellite markers spanning 60 centiMorgans (cM). Allele sharing identity by descent was examined in affected sib-pairs from these families, followed by multipoint sib-pair linkage analysis. Positive lod scores were obtained over a wide region (D6S470 to D6S271), with a maximum lod score of 2.2 occurring near D6S274, located in 6p22. However, we obtained a lod score of -2 at D6S296, the locus found by others to provide the greatest linkage evidence. At D6S274, we report a positive lod score as do Straub et al. (individually non-significant). A combined total lod of 3.6-4.0 suggests the possibility of a susceptibility locus in this region. However, methodological differences between our studies makes a firm conclusion difficult.

Genetic analysis of idiopathic torsion dystonia in Ashkenazi Jews and their recent descent from a small founder population.

We have examined data on six closely linked microsatellite loci on chromosome 9q34 from 59 Ashkenazi Jewish families with idiopathic torsion dystonia (ITD). Our data show that the vast majority (> 90%) of early-onset ITD cases in the Ashkenazi population are due to a single founder mutation, which we estimate first appeared approximately 350 years ago. We also show that carriers preferentially originate from the northern part of the historic Jewish Pale of settlement (Lithuania and Byelorussia). The recent origin of this dominant mutation and its current high frequency (between 1/6,000 and 1/2,000) suggest that the Ashkenazi population descends from a limited group of founders, and emphasize the importance of genetic drift in determining disease allele frequencies in this population.

Screening a large reference sample to identify very low frequency sequence variants: comparisons between two genes.

Most human sequence variation is in the form of single-nucleotide polymorphisms (SNPs). It has been proposed that coding-region SNPs (cSNPs) be used for direct association studies to determine the genetic basis of complex traits. The success of such studies depends on the frequency of disease-associated alleles, and their distribution in different ethnic populations. If disease-associated alleles are frequent in most populations, then direct genotyping of candidate variants could show robust associations in manageable study samples. This approach is less feasible if the genetic risk from a given candidate gene is due to many infrequent alleles. Previous studies of several genes demonstrated that most variants are relatively infrequent (<0.05). These surveys genotyped small samples (n<75) and thus had limited ability to identify rare alleles. Here we evaluate the prevalence and distribution of such rare alleles by genotyping an ethnically diverse reference sample that is more than six times larger than those used in previous studies (n=450). We screened for variants in the complete coding sequence and intron-exon junctions of two candidate genes for neuropsychiatric phenotypes: SLC6A4, encoding the serotonin transporter; and SLC18A2, encoding the vesicular monoamine transporter. Both genes have unique roles in neuronal transmission, and variants in either gene might be associated with neurobehavioral phenotypes.

Localization of a gene for partial epilepsy to chromosome 10q.

There is strong evidence for a genetic contribution to epilepsy, but it is commonly assumed that this genetic contribution is limited to 'generalized' epilepsies, and that most forms of 'partial' epilepsy are nongenetic. In a linkage analysis of a single family containing 11 affected individuals, we obtained strong evidence for localization of a gene for partial epilepsy. This susceptibility gene maps to chromosome 10q, with a maximum two-point lod score for D10S192 of 3.99 at theta = 0.0. All affected individuals share a single haplotype for seven tightly linked contiguous markers; the maximum lod score for this haplotype is 4.83 at theta = 0.0. Key recombinants place the susceptibility locus within a 10 centimorgan interval.

Multilocus linkage of familial hyperkalaemia and hypertension, pseudohypoaldosteronism type II, to chromosomes 1q31-42 and 17p11-q21.

Essential hypertension is a common multifactorial trait. The molecular basis of a number of rare diseases that after blood pressure in humans has been established, identifying pathways that may be involved in more common forms of hypertension. Pseudohypoaldosteronism type II (PHAII, also known as familial hyperkalaemia and hypertension or Gordon's syndrome; OMIM #145260), is characterized by hyperkalaemia despite normal renal glomerular filtration, hypertension and correction of physiologic abnormalities by thiazide diuretics. Mild hyperchloremia, metabolic acidosis and suppressed plasma renin activity are variable associated findings. The pathogenesis of PHAII is unknown, although clinical studies indicate an abnormality in renal ion transport. As thiazide diuretics are among the most efficacious agents in the treatment of essential hypertension, understanding the pathogenesis of PHAII may be of relevance to more common forms of hypertension. Analysis of linkage in eight PHAII families showing autosomal dominant transmission demonstrates locus heterogeneity of this trait, with a multilocus lod score of 8.1 for linkage of PHAII to chromosomes 1q31-q42 and 17p11-q21. Interestingly, the chromosome-17 locus overlaps a syntenic interval in rat that contains a blood pressure quantitative trait locus (QTL). Our findings provide a first step toward identification of the molecular basis of PHAII.

Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease.

Gene dosage of the apolipoprotein E (APOE) epsilon 4 allele is a major risk factor for familial Alzheimer disease (AD) of late onset (after age 60). Here we studied a large series of 115 AD case subjects and 243 controls as well as 150 affected and 197 unaffected members of 66 AD families. Our data demonstrate a protective effect of the epsilon 2 allele, in addition to the dose effect of the epsilon 4 allele in sporadic AD. Although a substantial proportion (65%) of AD is attributable to the presence of epsilon 4 alleles, risk of AD is lowest in subjects with the epsilon 2/epsilon 3 genotype, with an additional 23% of AD attributable to the absence of an epsilon 2 allele. The opposite actions of the epsilon 2 and epsilon 4 alleles further support the direct involvement of APOE in the pathogenesis of AD.

A second-generation screen of the human genome for susceptibility to insulin-dependent diabetes mellitus.

During the past decade, the genetics of type 1 (insulin-dependent) diabetes mellitus (IDDM) has been studied extensively and the disorder has become a paradigm for genetically complex diseases. Previous genome screens and studies focused on candidate genes have provided evidence for genetic linkage between polymorphic DNA markers and 15 putative IDDM susceptibility loci, designated IDDM1-IDDM15. We have carried out a second-generation screen of the genome for linkage and analysed the data by multipoint linkage methods. An initial panel of 212 affected sibpairs (ASPs) was genotyped for 438 markers spanning all autosomes, and an additional 467 ASPs were used for follow-up genotyping. Other than the well-established linkage with the HLA region at chromosome 6p21.3, there was only one region, located on chromosome 1q and not previously reported, where the log likelihood ratio (lod) was greater than 3. Lods between 1.0 and 1.8 were found in six other regions, three of which have been reported in other studies. Another reported region, on chromosome 6q and loosely linked to HLA, also had an elevated lod. Little or no support was found for most reported IDDM loci (lods were less than 1), despite larger sample sizes in the present study.

The early-onset torsion dystonia gene (DYT1) encodes an ATP-binding protein.

Early-onset torsion dystonia is a movement disorder, characterized by twisting muscle contractures, that begins in childhood. Symptoms are believed to result from altered neuronal communication in the basal ganglia. This study identifies the DYT1 gene on human chromosome 9q34 as being responsible for this dominant disease. Almost all cases of early-onset dystonia have a unique 3-bp deletion that appears to have arisen idependently in different ethnic populations. This deletion results in loss of one of a pair of glutamic-acid residues in a conserved region of a novel ATP-binding protein, termed torsinA. This protein has homologues in nematode, rat, mouse and humans, with some resemblance to the family of heat-shock proteins and Clp proteases.

A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis.

Hereditary haemochromatosis (HH), which affects some 1 in 400 and has an estimated carrier frequency of 1 in 10 individuals of Northern European descent, results in multi-organ dysfunction caused by increased iron deposition, and is treatable if detected early. Using linkage-disequilibrium and full haplotype analysis, we have identified a 250-kilobase region more than 3 megabases telomeric of the major histocompatibility complex (MHC) that is identical-by-descent in 85% of patient chromosomes. Within this region, we have identified a gene related to the MHC class I family, termed HLA-H, containing two missense alterations. One of these is predicted to inactivate this class of proteins and was found homozygous in 83% of 178 patients. A role of this gene in haemochromatosis is supported by the frequency and nature of the major mutation and prior studies implicating MHC class I-like proteins in iron metabolism.

A full genome search in multiple sclerosis.

The aetiology of multiple sclerosis (MS) is uncertain. There is strong circumstantial evidence to indicate it is an autoimmune complex trait. Risks for first degree relatives are increased some 20 fold over the general population. Twin studies have shown monozygotic concordance rates of 25-30% compared to 4% for dizygotic twins and siblings. Studies of adoptees and half sibs show that familial risk is determined by genes, but environmental factors strongly influence observed geographic differences. Studies of candidate genes have been largely unrewarding. We report a genome search using 257 microsatellite markers with average spacing of 15.2 cM in 100 sibling pairs (Table 1, data set 1 - DS1). A locus of lambda>3 was excluded from 88% of the genome. Five loci with maximum lod scores (MLS) of >1 were identified on chromosomes 2, 3, 5, 11 and X. Two additional data sets containing 44 (Table 1, DS2) and 78 sib pairs (Table 1, DS3) respectively, were used to further evaluate the HLA region on 6p21 and a locus on chromosome 5 with an MLS of 4.24. Markers within 6p21 gave MLS of 0.65 (non-significant, NS). However, D6S461, just outside the HLA region, showed significant evidence for linkage disequilibrium by the transmission disequilibrium test (TDT), in all three data sets (for DS1 chi2 = 10.8, adjusted P < 0.01)(DS2 and DS3 chi2 = 10.9, P < 0.0005), suggesting a modest susceptibility locus in this region. On chromosome 5p results from all three data sets (222 sib pairs) yielded a multipoint MLS of 1.6. The results support genetic epidemiological evidence that several genes interact epistatically to determine heritable susceptibility.

A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2.

Non-insulin-dependent (type 2) diabetes mellitus (NIDDM) is a common disorder of middle-aged individuals characterized by high blood glucose levels which, if untreated, can cause serious medical complications and lead to early death. Genetic factors play an important role in determining susceptibility to this disorder. However, the number of genes involved, their chromosomal location and the magnitude of their effect on NIDDM susceptibility are unknown. We have screened the human genome for susceptibility genes for NIDDM using non-and quasi-parametric linkage analysis methods in a group of Mexican American affected sib pairs. One marker, D2S125, showed significant evidence of linkage to NIDDM and appears to be a major factor affecting the development of diabetes mellitus in Mexican Americans. We propose that this locus be designated NIDDM1.

Cystic fibrosis mutations for p.F508del compound heterozygotes predict sweat chloride levels and pancreatic sufficiency.

Cystic fibrosis (CF) is a monogenetic disease with a complex phenotype. Over 1500 mutations in the CFTR gene have been identified; however, the p.F508del mutation is most common. There has been limited correlation between the CFTR mutation genotype and the disease phenotypes. We evaluated the non-p.F508del mutation of 108 p.F508del compound heterozygotes using the biological classification method, Grantham and Sorting Intolerant from Tolerant (SIFT) scores to assess whether these scoring systems correlated with sweat chloride levels, pancreatic sufficiency, predicted FEV(1) , and risk of infection with Pseudomonas aeruginosa in the last year. Mutations predicted to be 'mild' by the biological classification method are associated with more normal sweat chloride levels (p < 0.001), pancreatic sufficiency (p < 0.001) and decreased risk of infection with Pseudomonas in the last year (p = 0.014). Lower Grantham scores are associated with more normal sweat chloride levels (p < 0.001), and pancreatic sufficiency (p = 0.014). Higher SIFT scores are associated with more normal sweat chloride levels (p < 0.001) and pancreatic sufficiency (p = 0.011). There was no association between pulmonary function measured by predicted FEV(1) and the biological classification (p = 0.98), Grantham (p = 0.28) or SIFT scores (p = 0.62), which suggests the pulmonary disease related to CF may involve other modifier genes and environmental factors.

A brief note on the resemblance between relatives in the presence of population stratification.

Population stratification occurs when a study population is comprised of several sub-populations, and can result in increased false positive findings in genomewide-association studies. Recently published work shows that sub-population-specific positive assortative mating at the genotypic level results in population stratification. We show that if the allele frequency of a single nucleotide polymorphism responsible for a trait varies between sub-populations and there is no dominance variance, then the heritability of the trait increases, primarily due to an increase in the additive genetic variance of the trait.

An extremes of outcome strategy provides evidence that multiple sclerosis severity is determined by alleles at the HLA-DRB1 locus.

Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpassed for variability in disease outcome. A cohort of sporadic MS cases (n = 163), taken from opposite extremes of the distribution of long-term outcome, was used to determine the role of the HLA-DRB1 locus on MS disease severity. Genotyping sets of benign and malignant MS patients showed that HLA-DRB1*01 was significantly underrepresented in malignant compared with benign cases. This allele appears to attenuate the progressive disability that characterizes MS in the long term. The observation was doubly replicated in (i) Sardinian benign and malignant patients and (ii) a cohort of affected sibling pairs discordant for HLA-DRB1*01. Among the latter, mean disability progression indices were significantly lower in those carrying the HLA-DRB1*01 allele compared with their disease-concordant siblings who did not. The findings were additionally supported by similar transmission distortion of HLA-DRB1*04 subtypes closely related to HLA-DRB1*01. The protective effect of HLA-DRB1*01 in sibling pairs may result from a specific epistatic interaction with the susceptibility allele HLA-DRB1*1501. A high-density (>700) SNP examination of the MHC region in the benign and malignant patients could not identify variants differing significantly between the two groups, suggesting that HLA-DRB1 may itself be the disease-modifying locus. We conclude that HLA-DRB1*01, previously implicated in disease resistance, acts as an independent modifier of disease progression. These results closely link susceptibility to long-term outcome in MS, suggesting that shared quantitative MHC-based mechanisms are common to both, emphasizing the central role of this region in pathogenesis.