The human ␤2-adrenergic receptor gene has multiple single-nucleotide polymorphisms (SNPs), but the relevance of chromosomally phased SNPs (haplotypes) is not known. The phylogeny and the in vitro and in vivo consequences of variations in the 5 upstream and ORF were delineated in a multiethnic reference population and an asthmatic cohort. Thirteen SNPs were found organized into 12 haplotypes out of the theoretically possible 8,192 combinations. Deep divergence in the distribution of some haplotypes was noted in Caucasian, African-American, Asian, and Hispanic-Latino ethnic groups with >20-fold differences among the frequencies of the four major haplotypes. The relevance of the five most common ␤2-adrenergic receptor haplotype pairs was determined in vivo by assessing the bronchodilator response to ␤ agonist in asthmatics. Mean responses by haplotype pair varied by >2-fold, and response was significantly related to the haplotype pair (P ‫؍‬ 0.007) but not to individual SNPs. Expression vectors representing two of the haplotypes differing at eight of the SNP loci and associated with divergent in vivo responsiveness to agonist were used to transfect HEK293 cells. ␤2-adrenergic receptor mRNA levels and receptor density in cells transfected with the haplotype associated with the greater physiologic response were Ϸ50% greater than those transfected with the lower response haplotype. The results indicate that the unique interactions of multiple SNPs within a haplotype ultimately can affect biologic and therapeutic phenotype and that individual SNPs may have poor predictive power as pharmacogenetic loci.

Variation within genes has important implications for all biological traits. We identified 3899 single nucleotide polymorphisms (SNPs) that were present within 313 genes from 82 unrelated individuals of diverse ancestry, and we organized the SNPs into 4304 different haplotypes. Each gene had several variable SNPs and haplotypes that were present in all populations, as well as a number that were population-specific. Pairs of SNPs exhibited variability in the degree of linkage disequilibrium that was a function of their location within a gene, distance from each other, population distribution, and population frequency. Haplotypes generally had more information content (heterozygosity) than did individual SNPs. Our analysis of the pattern of variation strongly supports the recent expansion of the human population.

There is current interest in understanding genetic influences on both healthy and disordered brain function. We assessed brain function with functional magnetic resonance imaging (fMRI) data collected during an auditory oddball task-detecting an infrequent sound within a series of frequent sounds. Then, task-related imaging findings were utilized as potential intermediate phenotypes (endophenotypes) to investigate genomic factors derived from a single nucleotide polymorphism (SNP) array. Our target is the linkage of these genomic factors to normal/abnormal brain functionality. We explored parallel independent component analysis (paraICA) as a new method for analyzing multimodal data. The method was aimed to identify simultaneously independent components of each modality and the relationships between them. When 43 healthy controls and 20 schizophrenia patients, all Caucasian, were studied, we found a correlation of 0.38 between one fMRI component and one SNP component. This fMRI component consisted mainly of parietal lobe activations. The relevant SNP component was contributed to significantly by 10 SNPs located in genes, including those coding for the nicotinic a-7cholinergic receptor, aromatic amino acid decarboxylase, disrupted in schizophrenia 1, among others. Both fMRI and SNP components showed significant differences in loading parameters between the schizophrenia and control groups (P 5 0.0006 for the fMRI component; P 5 0.001 for the SNP component). In summary, we constructed a framework to identify interactions between brain functional and genetic information; our findings provide a proof-of-concept that genomic SNP factors can be investigated by using endophenotypic imaging findings in a multivariate format.

Opioids are mainly used to treat both acute and chronic pain. Several opioids are metabolized to some extent by CYP2D6 (codeine, tramadol, hydrocodone, oxycodone, and methadone). Polymorphisms in CYP2D6 have been studied for an association with the clinical effect and safety of these drugs. Other genes that have been studied for their association with opioid clinical effect or adverse events include OPRM1 (mu receptor) and COMT (catechol‐O‐methyltransferase). This guideline updates and expands the 2014 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 genotype and codeine therapy and includes a summation of the evidence describing the impact of CYP2D6, OPRM1, and COMT on opioid analgesia and adverse events. We provide therapeutic recommendations for the use of CYP2D6 genotype results for prescribing codeine and tramadol and describe the limited and/or weak data for CYP2D6 and hydrocodone, oxycodone, and methadone, and for OPRM1 and COMT for clinical use.

As of September 2019 there are 131 CYP2D6 core allele definitions (*1 through *139, eight alleles have been retired). a Evidence levels for these alleles were revised from "Lim" (Limited) or "Mod" (Moderate) to "Def" (Definitive).

The brain's default mode network (DMN) is highly heritable and is compromised in a variety of psychiatric disorders. However, genetic control over the DMN in schizophrenia (SZ) and psychotic bipolar disorder (PBP) is largely unknown. Study subjects (n = 1,305) underwent a resting-state functional MRI scan and were analyzed by a two-stage approach. The initial analysis used independent component analysis (ICA) in 324 healthy controls, 296 SZ probands, 300 PBP probands, 179 unaffected first-degree relatives of SZ probands (SZREL), and 206 unaffected first-degree relatives of PBP probands to identify DMNs and to test their biomarker and/ or endophenotype status. A subset of controls and probands (n = 549) then was subjected to a parallel ICA (para-ICA) to identify imaging-genetic relationships. ICA identified three DMNs. Hypoconnectivity was observed in both patient groups in all DMNs. Similar patterns observed in SZREL were restricted to only one network. DMN connectivity also correlated with several symptom measures. Para-ICA identified five sub-DMNs that were significantly associated with five different genetic networks. Several top-ranking SNPs across these networks belonged to previously identified, well-known psychosis/mood disorder genes. Global enrichment analyses revealed processes including NMDA-related long-term potentiation, PKA, immune response signaling, axon guidance, and synaptogenesis that significantly influenced DMN modulation in psychoses. In summary, we observed both unique and shared impairments in functional connectivity across the SZ and PBP cohorts; these impairments were selectively familial only for SZREL. Genes regulating specific neurodevelopment/transmission processes primarily mediated DMN disconnectivity. The study thus identifies biological pathways related to a widely researched quantitative trait that might suggest novel, targeted drug treatments for these diseases.genetics | BSNIP | architecture | molecular S chizophrenia (SZ) and psychotic bipolar disorder (PBP) are common, serious, heritable, genetically complex illnesses, sharing multiple characteristics, including risk genes and abnormalities in cognition, neural function, and brain structure (1-4). However, despite recent advances, their underlying biological mechanisms are largely undetermined and may be shared across the two diagnostic groups. Recent large-scale analyses have used various statistical informatics strategies to dissect these biological underpinnings better (5, 6). A recent study using a pathwayenrichment strategy showed that genes involved in neuronal cell adhesion, synaptic formation, and cell signaling are overrepresented in SZ and bipolar disorder (BP) (6). Another study using an informatics-based approach identified several cohesive genetic networks related to axon guidance, neuronal cell mobility, and synaptic functioning as key players in schizophrenia (5).Although risk for psychotic illnesses is driven in small part by highly penetrant, often private mutations such as copy number variants, substantial...

Haplotype analysis has become increasingly important for the study of human disease as well as for reconstruction of human population histories. Computer programs have been developed to estimate haplotype frequencies statistically from marker phenotypes in unrelated individuals. However, there currently are few empirical reports on the accuracy of statistical estimates that must infer linkage phase. We have analyzed haplotypes at the CD4 locus on chromosome 12 that consist of a short tandem-repeat polymorphism and an Alu insertion/deletion polymorphism located 9.8 kb apart, in 398 individuals from 10 geographically diverse sub-Saharan African populations. Haplotype frequency estimates obtained using gene counting based on molecularly haplotyped (phase-known) data were compared with haplotype frequency estimates obtained using the expectation-maximization algorithm. We show that the estimated frequencies of common haplotypes do not differ significantly with the use of phase-known versus phase-unknown data. However, rare haplotypes are occasionally miscalled when their presence/absence must be inferred. Thus, for those research questions for which the common haplotypes are most important, frequency estimates based on the phase-unknown marker-typing results from unrelated individuals will be sufficient. However, in cases where knowledge of rare haplotypes is critical, molecular haplotyping will be necessary to determine linkage phase unambiguously.

We have developed a reliable method for the direct resolution of haplotypes or linkage phase from individuals who are multiply heterozygous in a given genomic region. The method is based on single-molecule dilution (SMD) of genomic template and amplification via biphasic polymerase chain reaction (booster PCR). We have verified the feasibility of the SMD method for a highly polymorphic region within the (3-globin cluster by analysis of triply heterozygous individuals of known haplotype. This approach should be useful in many studies in population or evolutionary genetics and in a variety of clinical settings.Over the past half century, the discipline of population genetics has evolved from the theory-driven era of Fisher, Haldane, and Wright into an enterprise driven by molecular data. This transformation was punctuated by experimental insights and breakthroughs that allowed the phenotypes being monitored to more directly represent their underlying genetic basis. Critical phases in this progression are work on Drosophila pseudoobscura chromosomal inversions by Dobzhansky and his colleagues (1), protein electrophoretic studies (2), mitochondrial DNA studies (3), and now the potential for direct analysis of DNA variants. The tremendous wealth of variability at the DNA level would seem to provide the potential to answer many longstanding questions in population genetics (4). However, this level of resolution also poses many new questions. In particular, a view of polymorphic sites as simple independent markers is inadequate in discussions of the evolutionary history of any given gene or genomic region. The number of polymorphic sites and the linkage disequilibrium among them requires such discussions to focus on the DNA "haplotypes" at a locus. A specific DNA haplotype is the specific combination of variants at each of the polymorphic sites being studied. If one thinks of haplotypes as being the alleles at a locus, there is now an added dimension compared to, say, electrophoretic alleles-the possibility of addressing evolutionary relationships among alleles.The high levels of polymorphism and consequent heterozygosity pose a problem in this regard-ambiguity of which haplotypes are present in any given diploid organism. This is due to the frequent occurrence of multiple heterozygous sites in a given individual. With two heterozygous sites there are four possible haplotypes and the number of possible haplotypes doubles for each additional heterozygous site in the individual. Ideally, an individual's genotype across multiple heterozygous loci should include resolution into the two constituent haplotypes.Classically, haplotypes in multiply heterozygous individuals or organisms have been resolved by pedigree analysis, breeding programs, or such special attributes as a haploid sex, depending on the organism. In humans, family studies have been the basis for determining haplotypes at loci such as phenylalanine hydroxylase (5) and the ,3-globin cluster (6).