As technical barriers to human DNA sequencing decrease and the cost of whole-genome sequencing (WGS) approaches $1000, WGS and protein-coding genome sequencing (whole-exome sequencing [WES]) are increasingly used in clinical medicine. Both WGS/WES can successfully aid clinical diagnosis,^1-3 reveal the genetic basis of rare familial diseases,^4-6 and explicate novel disease biology.^7,8 Regardless of context, even in apparently healthy individuals, WGS/WES are expected to uncover genetic findings of potential clinical importance.^9-11 However, comprehensive clinical interpretation and reporting of clinically significant findings are seldom performed. As WGS/WES are applied more broadly, questions have been raised about the duty for discovery, interpretation, and reporting of clinical findings. Recently published recommendations define genetic variant types in a minimum list of inherited disease genes that are suggested to be subject to discovery, reporting, and clinical follow-up regardless of the primary indication for sequencing, patient preference, or patient age.¹² Despite this, the technical sensitivity and reproducibility of clinical genetic findings using WGS and the clinical opportunities and costs associated with discovery and reporting of these and other clinical findings in WGS data remain undefined.

In humans, 5-HT_1Areceptors are implicated in anxiety and depressive disorders and their treatment. However, the physiological and genetic factors controlling 5-HT_1Areceptor expression are undetermined in health and disease. In this study, the influence of two genetic factors on 5-HT_1Areceptor expression in the living human brain was assessed using the 5-HT_1A-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-HT_1Areceptor gene, the influence of the common SNP [(-1018) C>G] on 5-HT_1Areceptor 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-HT_1Areceptor density. Whereas, the 5-HT_1Areceptor genotype did not show any significant effects on [¹¹C]WAY 100635 binding, 5-HT_1Areceptor 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-HT_1Areceptor gene, affects 5-HT_1Areceptor availability in man. The results may offer a plausible physiological mechanism underlying the association between 5-HTTLPR genotype, behavioral traits, and mood states.

Cigarette smoking continues to contribute substantially to US morbidity and mortality, despite increasingly stringent public health measures that make it more difficult and expensive to smoke.¹ Smokers may thus now include many who have considerable difficulty in achieving sustained abstinence from tobacco, despite the availability of therapeutic drugs that act at sites that include nicotinic receptors and monoamine transporters.² Understanding the mechanisms that facilitate or impede smokers' abilities to achieve and sustain abstinence from smoking could thus inform a major current US public health problem and augment understanding of mnemonic and other brain mechanisms that might influence abstinence.³ Understanding mechanisms that contribute to the abstinence-enhancing efficacies of specific therapeutic drugs could help match smokers with treatments that would be more likely to be effective for them.