Significant Differences In Allele Distributions Research Articles

The NAD(P)H:Quinone Oxidoreductase (NQO1) C609T Polymorphism Is Found at Variable Frequency in Different Ethnic Groups but Does Not Predispose to De Novo AML in Israel.

Background: The NQO1 gene is located on chromosome 16q22.1. This gene encodes a cytosolic enzyme which is expressed in many tissues including the hematopoietic system. NQO1 has an important role in detoxifying quinones, which are widespread compounds that are present thoughout the body (vitamin K), the diet (proteins, fruits and vegetables) and the environment (solvents, cosmetics, cigarette smoke). A single nucleotide polymorphism (C to T) at position 609 (NQO1*2) produces a proline to serine substitution at codon 187 and results in very reduced enzyme activity (null allele). Wild type genotype individuals have normal NQO1 activity, heterozygotes have reduced activity and homozygotes for the mutation have nearly absent activity. The polymorphism is present at varying frequencies in different ethnic groups throughout the world. Several reports have shown an association of this polymorphism and susceptibility to nonhematological malignancies such as lung cancer in smokers. Other reports have found that it is associated with de novo adult AML, therapy-related AML, infant leukemia with MLL rearrangements and benzene-induced hematotoxicity/leukemia.Aims: To determine the frequency of the NQO1*2 allele in Israeli ethnic groups and to determine if the allele predisposes to de novo adult AML in Israeli patients.Methods: We used PCR to analyze for the presence of the NQO1*2 allele, utilizing the methodology of MT Smith (Blood 2001) with nested PCR and digestion with Hinf1. We studied adult AML patients of different ethnic origins (156 Jews and 106 Arabs) and normal controls of three major ethnic groups in Israel (270 Caucasian Jews, 250 Arabs and 168 Ethiopian Jews). Too few Ethiopian adult AML patients were identified to be included in the analysis.Results: In the control Arab group, the distribution of the alleles was: homozygous normal (CC) 54%, heterozygotes (CT) 38.5%, and homozygous mutant (TT) 7.5%, which was virtually identical to the distribution in Arab AML patients (CC 52.8%, CT 41.5% and TT 5.7%). Similarly, the distribution in Caucasian Jewish controls was: CC 60.8%, CT 37.2%, and TT 2%, virtually identical to CC 61.1%, CT 35% and TT 3.9% in Caucasian AML patients. Ethiopian controls had a very different allelic distribution: CC 72.6%, CT 26.2% and TT 1.1 %. While the differences among the various ethnic groups was highly statistically significant, there were no statistically significant differences in allelic frequencies of patients as compared to ethnic matched controls.Conclusions: In Israel there are significant differences in allelic distribution of NQO1 among various ethnic groups. However, the null allele was not present at a higher frequency in patients, suggesting that the null allele did not predispose to the development of de novo adult AML in Israel. The reason for the discrepancy between our data and other published studies may relate to underlying genetic differences in our population, for example, in CYP2E1, which participates in the same metabolic pathways as NQO1. Alternatively, it is possible that NQO1 protects against de novo AML only under specific environmental conditions, which may not exist in Israel. Our findings emphasize the importance of cross-cultural validation of pharmacogenetic studies, in order to assure the reliability of the findings.

Association of DAAO with schizophrenia in the Chinese population

Recently, the gene called DAAO was reported to be associated with schizophrenia in the French Canadian populations. Here, we report a result obtained in the study of our large collection of 547 schizophrenia cases and 536 controls in the Chinese population. Six single-nucleotide polymorphisms (SNPs) were genotyped at and around the DAAO locus, covering a 10-kb region entirely encompassing the complementary DNA sequences of DAAO. We found statistically significant differences in allele distributions on one marker: SNP rs3741775 ( P = 0.0000001). In the haplotype analysis based on the information of linkage-disequilibrium block across this gene locus, we demonstrated a highly significant association between schizophrenia and a DAAO haplotype ( P = 2.0173 × 10 −21), which therefore provides an independent statistical support for association of the DAAO gene with schizophrenia and indicates that the DAAO gene may play a significant role in the etiology of schizophrenia in the Han Chinese.

Association of G72/G30 with schizophrenia in the Chinese population

Recently, the G72 gene was reported to be associated with schizophrenia in the French Canadian and Russian populations. Here, we report the results obtained from the study of six single-nucleotide polymorphisms (SNPs: rs3916965, rs3916967, rs2391191, rs1935062, rs778293, and rs3918342), which span an 82-kb region covering the complementary DNA sequences of G72 and G30, in 537 schizophrenia cases and 538 controls of the Han Chinese. In this work, we have identified statistically significant differences in allele distributions of two markers rs3916965 ( P=0.019) and rs2391191 ( P=0.0010), and a highly significant association between haplotype AGAC of the G72/G30 locus ( P=1.7×10 −4) and schizophrenia. Our data provide further evidence that markers of the G72/G30 genes are associated with schizophrenia in a non-Caucasian population.

Calpain-10 haplotype combination and association with gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is a frequent complication of pregnancy. Epidemiologic and pathophysiologic data suggest a close link of this disease to non-insulin-dependent diabetes mellitus. Within the calpain-10 gene various single-nucleotide polymorphisms have been identified that increased the risk for non-insulin-dependent diabetes mellitus. Therefore, we examined single-nucleotide exchanges of this gene in women with GDM. A total of 875 unselected women were prospectively screened for GDM. Eighty women of this population, 40 patients with an abnormal oral glucose tolerance test and 40 normal controls, were randomly selected. DNA samples isolated from sera of the control and study groups were analyzed with respect to single-nucleotide polymorphisms of the calpain-10 gene at positions 43, 19, and 63 using polymerase chain reaction amplification and restriction analysis. Women with GDM were more likely to be homozygous for the allele 1 of single-nucleotide polymorphism 63 (P =.02 by chi(2) test). With respect to single-nucleotide polymorphisms 19 and 43, no significant differences in allele distribution were detected between controls and women with GDM. When comparing the different haplotypes for calpain-10 (single-nucleotide polymorphisms 43, 19, and 63), all women with the haplotype combination 121/221 (n = 8) had gestational diabetes (P =.005 by Fisher exact test). Our results indicate that the haplotype 121/221 of the calpain-10 gene may be associated with disturbances of glucose metabolism during pregnancy. II-1

A microsatellite polymorphism in intron 2 of human Toll-like receptor 2 gene: functional implications and racial differences

The human Toll-like receptor 2 (TLR2) mediates responses of both innate and adaptive immunity to Gram-positive bacteria, including mycobacteria. We sought functional polymorphisms in the 5′-untranslated region (UTR) of TLR2. We found a highly polymorphic (GT) n dinucleotide repeat 100 bp upstream of the TLR2 translational start site in intron 2. The numbers of GT repeats varied from 12 to 28. There were significant differences in allele distribution between African Americans and Caucasians ( P=0.008) and between African Americans and Koreans ( P=0.0003). The promoter activities of recombinant promoter–intron2/reporter constructs including the shortest [GT) n=12] or longest [(GT) n=28] alleles were significantly more stimulated when exposed to 200 IU ml −1 of interferon-γ than when exposed to 100 IU ml −1 of GM-CSF ( P≤0.03). Since TLR2 plays a critical role in the human innate immune response, this functional microsatellite polymorphism may be important in the pathogenesis of infectious and inflammatory diseases.

Molecular analysis of the oligodendrocyte myelin glycoprotein gene in autistic disorder

We previously observed in four autistic patients a new allele (GXAlu 5) of the GXAlu microsatellite marker located in intron 27b of the neurofibromatosis type 1 (NF1) gene (17q11.2). This large intron contains the OMGP gene, coding for the oligodendrocyte myelin glycoprotein expressed by neurons and oligodendrocytes. In the present work, we analysed the distribution of a coding single nucleotide polymorphism (OMGP62) of the OMGP gene, the nearest gene to the GXAlu marker, in a control population (n=101) and in an autistic group (n=65). We observed no significant difference in allele distribution comparing these two groups (χ2=1.81; P=0.179). When distinguishing an autistic group with a developmental quotient (DQ) higher than 30 (n=37) and one with a DQ lower than 30 (n=28), we observed an association between allele A and the group with the highest DQ (P=0.015). We found no other polymorphism using SSCP screening and DNA sequencing in the OMGP coding region in 16 autistic patients bearing OMGP62 allele A.

Molecular analysis of the oligodendrocyte myelin glycoprotein gene in autistic disorder

We previously observed in four autistic patients a new allele (GXAlu 5) of the GXAlu microsatellite marker located in intron 27b of the neurofibromatosis type 1 ( NF1) gene (17q11.2). This large intron contains the OMGP gene, coding for the oligodendrocyte myelin glycoprotein expressed by neurons and oligodendrocytes. In the present work, we analysed the distribution of a coding single nucleotide polymorphism (OMGP62) of the OMGP gene, the nearest gene to the GXAlu marker, in a control population ( n=101) and in an autistic group ( n=65). We observed no significant difference in allele distribution comparing these two groups (χ 2=1.81; P=0.179). When distinguishing an autistic group with a developmental quotient (DQ) higher than 30 ( n=37) and one with a DQ lower than 30 ( n=28), we observed an association between allele A and the group with the highest DQ ( P=0.015). We found no other polymorphism using SSCP screening and DNA sequencing in the OMGP coding region in 16 autistic patients bearing OMGP62 allele A.

QTL affecting body weight in a candidate region of cattle chromosome 5

The objective of this work was to identify QTLs for liveweight in a candidate region of bovine chromosome 5. Half-sib families from two lines, one traditional and the other new, of Canchim beef cattle (5/8 Charolais + 3/8 Zebu) were genotyped for four microsatellite markers, including the microsatellite in the IGF-1 (insulin-like growth factor-1) promoter region. Significant differences in allele distribution between the two lines were found for three markers. Interval mapping analyses in this region indicated the presence of a QTL controlling birth weight (p < 0.05) and of a QTL influencing breeding value for yearling weight (p < 0.01) in the newer line of the breed. The previously identified interaction between the IGF-1 genotype and genetic group strengthens the hypothesis of a linked QTL rather than an IGF-1 effect on growth traits in the Canchim cattle.

Y chromosome microsatellite variation in three populations of Jerba Island (Tunisia)

Six Y‐chromosome linked microsatellites were typed in a sample of 135 unrelated males representing three different ethnic groups: Arabs, Berbers and Blacks of Jerba Island (Tunisia). Analysis of variation at the six Y chromosome STRs showed significant differences in allele distributions between the Black group and the two other Islander groups. The Black group revealed the highest level of genetic diversity as compared to Arabs and Berbers, while the latter group was the most homogenous. Allele frequencies obtained for the three islander groups analysed were compared to data available for some European, Mediterranean and African populations. Principal‐coordinate analyses showed genetic differentiation between the three geographically closed groups of Jerba. The absence of the YAP insertion marker and the position of Arabs and Jerban Blacks near the European cluster would suggest their relative ‘admixture’ with European populations.

Y chromosome microsatellite variation in three populations of Jerba Island (Tunisia).

Six Y-chromosome linked microsatellites were typed in a sample of 135 unrelated males representing three different ethnic groups: Arabs, Berbers and Blacks of Jerba Island (Tunisia). Analysis of variation at the six Y chromosome STRs showed significant differences in allele distributions between the Black group and the two other Islander groups. The Black group revealed the highest level of genetic diversity as compared to Arabs and Berbers, while the latter group was the most homogeneous. Allele frequencies obtained for the three islander groups analysed were compared to data available for some European, Mediterranean and African populations. Principal-coordinate analyses showed genetic differentiation between the three geographically closed groups of Jerba. The absence of the YAP insertion marker and the position of Arabs and Jerban Blacks near the European cluster would suggest their relative 'admixture' with European populations.

Analysis of the NRAMP1 Gene Implicated in Iron Transport: Association with Multiple Sclerosis and Age Effects

ABSTRACTMultiple sclerosis (MS) is believed to be an autoimmune process occurring in genetically susceptible individuals after an appropriate environmental exposure. We have exploited the homogeneous Afrikaner population of European ancestry to investigate the likelihood that iron dysregulation, in association with infectious and/or autoimmune disease susceptibility, may underlie the MS phenotype in a subgroup of patients. The functional Z-DNA forming repeat polymorphism of the natural resistance-associated macrophage protein-1 (NRAMP1) gene was analyzed in 104 patients diagnosed with MS and 522 Caucasian controls. A family-based control group consisting of 32 parental alleles not transmitted to MS offspring was additionally studied to exclude the likelihood of population substructures. Statistically significant differences in allelic distribution were observed between the patient and control samples drawn from the same population (P < 0.01). Evidence is furthermore provided that alleles considered to be detrimental in relation to autoimmune disease susceptibility may be maintained in the population as a consequence of improved survival to reproductive age following infectious disease challenge. Although it remains to be determined whether the disease phenotype in MS patients with allele 5 of the NRAMP1 promoter polymorphism is directly related to dysregulation of iron or modified susceptibility to viral infection and/or autoimmunity, a combination of these processes most likely underlies the disease phenotype in these patients. In view of the emerging role of polymorphic variants in complex diseases and minimizing of possible confounding factors in this association study, we conclude that allelic variation in the NRAMP1 promoter may contribute significantly to MS susceptibility in the South African Caucasian population.

Age-associated accumulation of the apolipoprotein C-III gene T-455C polymorphism C allele in a Russian population.

Apolipoprotein C-III (apoC-III) is the major component of triglyceride-rich lipoproteins. One of six identified polymorphisms in the apoC-III 5'-untranslated region (T-455C) is located within a functional insulin-response element. In a group of 137 elderly individuals (70-106 years old), the allele distribution was analyzed using restriction fragment length polymorphisms. Statistical analysis of allele frequencies was performed on subgroups selected by age and in elderly patients with arterial hypertension or ischemic heart disease. A greater frequency of the apoC-III -455C allele was demonstrated with aging (p < .005). No statistically significant difference in allele distributions was detected between healthy subjects and groups of elderly patients of the same age with either ischemic heart disease or arterial hypertension. The increased incidence of the C allele with advanced age indicates that this variant promoter is associated with longevity. The greater incidence of this allele is detectable only in adults older than 80 years of age.

Association of retinopathy with a microsatellite at 5' end of the aldose reductase gene in Chinese patients with late-onset Type 2 diabetes

Recent experimental data suggest that a microsatellite polymorphism at 5' end of the aldose reductase gene may be associated with the development of diabetic retinopathy. In the present study, we examined the allele distribution of the polymorphism in 384 Hong Kong Chinese patients who had late-onset (age at diagnosis =35 years) Type 2 diabetes, but no clinical evidence of cataract. Approximately 17% of them (n = 64) had retinopathy. The patients with retinopathy were older (52 ± 11 years vs. 60 ± 9 years, p < 0.01) and had a higher HbA 1c (8.9 ± 2.2% vs. 7.7 ± 2.0%, p < 0.01 with adjustment for age) than those without the complication. Amongst all of the patients, we detected 10 microsatellite alleles and found that allele Z-4 was overpresented in those with retinopathy (9% vs. 4%, p < 0.05). There were no significant differences in allelic distributions of the major alleles Z + 2, Z, and Z-2, which accounted for more than 80% of the overall frequency, between the two groups of patients. Using multiple logistic regression analysis (R 2 = 0.17, p < 0.01), we found that age (p < 0.01) and HbA 1c (p < 0.05) were associated with retinopathy. In conclusion, our data suggest that the occurrence of diabetic retinopathy in the Chinese population may be influenced by clinical and metabolic factors. The aldose reductase gene may be implicated, but is not likely to play a major role.

Allelic association between the DRD2 TaqI A polymorphism and Parkinson's disease.

Genes encoding proteins involved in dopaminergic transmission have been of special interest during the evaluation of candidate genes for Parkinson's disease (PD). The dopamine D2 receptor gene (DRD2) is located on chromosome 11 q22-q23, and several polymorphisms of the gene have been described. The DRD2 gene has a TaqI A restriction fragment length polymorphism that is located in the untranslated region, approximately 10 kilobases from the 3' end of the gene. This polymorphism creates the two alleles A1 (variant) and A2. In this study, we investigated the hypothesis that a TaqI repeat fragment length polymorphism in the dopamine D2 receptor gene may be associated with PD. DNA from 72 patients with PD, classified as definite, probable, or atypical PD, and from 81 controls was genotyped by polymerase chain reaction and gel electrophoresis for the presence of the TaqI A1 polymorphism. The controls were matched for age, race, and geographic origin. There were significant differences in allelic distribution between the overall PD group and control groups (chi2 = 5.009, p = 0.025). When only patients with definite PD were considered an even more significant association was found (chi2 = 8.2121, p = 0.004). Among the overall PD group, the odds ratio for having the variant allele A1 was found to be 2.2 (95% confidence interval, [1.1; 4.4]), whereas it was calculated to be 3.0 (95% confidence interval, [1.4; 6.4]) when only patients with definite PD were considered. The current study showed that there is a statistically significant association between the DRD2 variant allele A1 and PD. This association is most pronounced in patients with definite PD and becomes nonsignificant when the clinical picture is classified as atypical PD.

Possible association between serotonin transporter gene polymorphism and violent suicidal behavior in mood disorders

Background: Genes involved in the serotonin system are major candidates in association studies of suicidal behavior. In this case–control study we investigated whether the serotonin transporter (5-HTT) gene encoding the protein responsible for the reuptake of serotonin from the synapse after its release from serotonergic neurons is a susceptibility factor for suicidal behavior. Methods: A functional polymorphism of the 5-HTT gene (a 44–base pair insertion/deletion in the 5-HTT–linked polymorphic region [5-HTTLPR]) was studied in a population of 237 consecutive patients with affective disorder (unipolar or bipolar) and 187 control subjects. Ninety-nine patients had attempted suicide at least once, of whom 26 made a violent attempt. Results: No association was found between the “s” allele of the 5-HTTLPR and suicide attempt; however, there was a significant difference in allele distributions between patients who had made violent suicide attempts and control subjects. Conclusions: A genetic variant of the 5-HTT gene may predispose individuals to violent suicidal behavior. The precise phenotype associated with the 5-HTT gene is unclear, and therefore further studies are required to replicate these findings.

Using Genetics to Identify Intraspecific Conservation Units: a Critique of Current Methods

Genetic criteria have recently been proposed for identifying evolutionarily significant units (ESUs) and management units (MUs; Moritz 1994). Although this proposal has proved useful for focusing discussion about the intraspecific groupings of relevance to conservation, I am concerned that the criteria put forward have been accepted and applied without sufficient debate about their merit or limitations. My aim is to stimulate renewed debate on this subject by identifying some weaknesses in the proposed criteria. Although Moritz (1994) distinguished between the biological definitions of ESUs and MUs and the genetic criteria he proposed for recognizing such groups, many papers that cite his work erroneously refer to the recognition criteria as the definitions. An ESU is a group of organisms that has been isolated from other conspecific groups for a sufficient period of time to have undergone meaningful genetic divergence from those other groups (Ryder 1986). Moritz (1994) suggested that ESUs could be identified genetically as groups whose mtDNA lineages were reciprocally monophyletic, meaning that all lineages within each group share more-recent common ancestors than any lineage from one group shares with any lineage from the other group. In contrast, an MU is a group in which local population dynamics are determined primarily by birth and death rather than immigration and emigration (Moritz et al. 1995). Moritz (1994) suggested that MUs could be identified as populations with significant differences in allele distributions. An important point regarding both of these concepts is that they apply only when the populations under study are naturally divided into groups (Moritz et al. 1995). Of course, genetic study may also be of value in situations where populations are continuously distributed, but such populations cannot be subdivided into ESUs and MUs.

Association of an (A-C)n dinucleotide repeat polymorphic marker at the 5'-region of the aldose reductase gene with retinopathy but not with nephropathy or neuropathy in Japanese patients with Type 2 diabetes mellitus.

Recently an (A-C)n dinucleotide repeat polymorphic marker in the 5'-region of the ALR2 gene encoding aldose reductase was found to be associated with diabetic retinopathy in the Chinese population in Hong Kong, and with nephropathy and neuropathy in the British Caucasian population. The present study assessed the association between the polymorphism and microvascular complications in Japanese patients with Type 2 diabetes mellitus. DNA from 87 Japanese patients with Type 2 diabetes mellitus and 90 control subjects with normal glucose tolerance were typed for the polymorphic marker by polymerase chain reaction and direct sequencing. Six alleles, namely Z-12, Z-6, Z-4, Z-2, Z, and Z+2 were identified. There was no significant difference in allele distribution between diabetic patients and controls. The Z-2 allele frequency was significantly higher in subjects with diabetic retinopathy than those without retinopathy (0.35 vs. 0.20, P=0.039), suggesting that aldose reductase is involved in the development of diabetic retinopathy. In contrast, the microsatellite marker was not associated with diabetic nephropathy, peripheral or autonomic neuropathy. The discrepancy may be partly attributable to the low frequency of Z+2 allele in the Japanese subjects. The (A-C)n dinucleotide repeat polymorphism may be a useful genetic marker to screen for patients at high risk of retinopathy.

Lack of association between genetic variations of apo A-I–C-III–A-IV gene cluster and myocardial infarction in a sample of European male: ECTIM study

The goal of the present study was to compare the allele frequency of four polymorphisms at the apo A-I C-III A-IV cluster gene locus—ApoA-I: XmnI and PstI; ApoC-III: SstI; ApoA-IV: XbaI—between male patients who had had a myocardial infarction ( n=614) and matched controls ( n=764). The association with a number of lipid lipoprotein, apolipoprotein and lipoprotein particle variables was also assessed. Patients and subjects were recruited in Belfast, Lille, Strasbourg and Toulouse in the framework of the ECTIM study. In the control group, the frequencies of the different polymorphic alleles were homogeneous among recruitment centres suggesting the absence of any European North to South gradient for these cluster polymorphisms. There was no evidence for a significant difference in allelic distribution between cases and controls suggesting that apo A-I, C-III, A-IV gene cluster polymorphisms do not explain MI survival in this sample of European men. There was no statistically significant association between apo A-I C-III A-IV cluster gene polymorphisms and lipid, lipoprotein, apolipoprotein, and lipoprotein particle levels. In conclusion, in the ECTIM study, the apo A-I, C-III, A-IV gene cluster polymorphism is associated with neither circulating plasma variables nor MI survival.

Constitutional genetic variation at the human aromatase gene (Cyp19) and breast cancer risk.

The activity of the aromatase enzyme, which converts androgens into oestrogens and has a major role in regulating oestrogen levels in the breast, is thought to be a contributing factor in the development of breast cancer. We undertook this study to assess the role of constitutional genetic variation in the human aromatase gene (Cyp19) in the development of this disease. Our genotyping of 348 cases with breast cancer and 145 controls (all Caucasian women) for a published tetranucleotide repeat polymorphism at intron 4 of the Cyp19 gene revealed the presence of six common and two rare alleles. Contingency table analysis revealed a significant difference in allelic distribution between cases and controls (χ2 5df = 13.52, P = 0.019). The allele measuring 171 bp was over-represented in cases; of 14 individuals homozygous for this allele, 13 were cases. These individuals had a higher incidence of cancer in family members and an earlier age at diagnosis than other cases. In sequencing Cyp19's coding exons and regulatory regions, we discovered a perfect association between a silent polymorphism (G→A at Val80) and the high-risk genotype. Our conclusion is that constitutional genetic variation at the Cyp19 locus is associated with the risk of developing breast cancer, with the 171-bp allele serving as the high-risk allele. © 1999 Cancer Research Campaign

Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: possible implications for opiate addiction.

Opioid drugs play important roles in the clinical management of pain, as well as in the development and treatment of drug abuse. The mu opioid receptor is the primary site of action for the most commonly used opioids, including morphine, heroin, fentanyl, and methadone. By sequencing DNA from 113 former heroin addicts in methadone maintenance and 39 individuals with no history of drug or alcohol abuse or dependence, we have identified five different single-nucleotide polymorphisms (SNPs) in the coding region of the mu opioid receptor gene. The most prevalent SNP is a nucleotide substitution at position 118 (A118G), predicting an amino acid change at a putative N-glycosylation site. This SNP displays an allelic frequency of approximately 10% in our study population. Significant differences in allele distribution were observed among ethnic groups studied. The variant receptor resulting from the A118G SNP did not show altered binding affinities for most opioid peptides and alkaloids tested. However, the A118G variant receptor binds beta-endorphin, an endogenous opioid that activates the mu opioid receptor, approximately three times more tightly than the most common allelic form of the receptor. Furthermore, beta-endorphin is approximately three times more potent at the A118G variant receptor than at the most common allelic form in agonist-induced activation of G protein-coupled potassium channels. These results show that SNPs in the mu opioid receptor gene can alter binding and signal transduction in the resulting receptor and may have implications for normal physiology, therapeutics, and vulnerability to develop or protection from diverse diseases including the addictive diseases.