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Evidence for HTR1A and LHPP As Interacting Genetic Risk Factors In Molecular Psychiatry (2009) 14, 621–630 & 2009 Nature Publishing Group All rights reserved 1359-4184/09 $32.00 www.nature.com/mp ORIGINAL ARTICLE Evidence for HTR1A and LHPP as interacting genetic risk factors in major depression CD Neff1, V Abkevich1, JCL Packer2, Y Chen1, J Potter1, R Riley1, C Davenport1, J DeGrado Warren1, S Jammulapati1, A Bhathena2, WS Choi2, PE Kroeger2, RE Metzger2, A Gutin1, MH Skolnick1, D Shattuck1 and DA Katz2 1Myriad Genetics, Salt Lake City, UT, USA; 2Abbott Laboratories, Abbott Park, IL, USA The HTR1A À1019C > G genotype was associated with major depression in the Utah population. Linkage analysis on Utah pedigrees with strong family histories of major depression including only cases with the HTR1A À1019G allele revealed a linkage peak on chromosome 10 (maximum HLOD = 4.4). Sequencing of all known genes in the linkage region revealed disease-segregating single-nucleotide polymorphisms (SNPs) in LHPP. LHPP SNPs were also associated with major depression in both Utah and Ashkenazi populations. Consistent with the linkage evidence, LHPP associations depended on HTR1A genotype. Lhpp or a product of a collinear brain-specific transcript, therefore, may interact with Htr1a in the pathogenesis of major depression. Molecular Psychiatry (2009) 14, 621–630; doi:10.1038/mp.2008.8; published online 12 February 2008 Keywords: genetic linkage; genetic association; major depression; serotonin receptor; epistasis Introduction Currently available antidepressants work primarily by increasing the activity of the neurotransmitters, Mood disorders, of which major depressive disorder serotonin and norepinephrine, in synapses.5 Some (MDD) is the most common, affect one person in five medications inhibit the degradation of these mole- during their lifetime. The World Health Organization cules, others decrease removal of neurotransmitters estimates that depression is currently the fourth most from the synaptic space, and some medications important worldwide cause of disability-adjusted life stimulate norepinephrine release or inhibit negative year loss, and that it will become the second most feedback of serotonin signaling. Because these med- important cause by 2020.1 Pharmaceutical treatment ications are all based on a single principle, the of depression is frequently inadequate. Using the strength and range of their efficacy is similar. The current best treatments, one-third of patients or more improvements of the last half-century have involved do not achieve remission even after several months of the development of safer and more tolerable drugs. treatment.2 When today’s drugs do help patients However, despite this, today’s drugs are neither achieve remission from their depression, the onset completely safe nor completely tolerable for many of action is over a period of weeks, and there appears patients. There is considerable need for new drugs to be an increased risk of suicide during initial that are effective in a broader range of patients antidepressant therapy, although this risk may be less (particularly for patients whose depression is resis- than that just prior to therapy initiation.3 Further- tant to available pharmaceuticals), that have a faster more, there are high recurrence rates—approximately onset of action, that are safer and more tolerable or 85% of patients who achieve remission will suffer that complement the efficacy of existing drugs. It is another episode of MDD.4 Finally, currently available unlikely that a substantial further improvement in antidepressants are associated with side effects that any of these dimensions will be achieved through the lead some patients to stop taking their medications at development of additional serotonergic or noradre- risk of sinking back (further) into depression, and to nergic agents. morbidity in others.5 Identifying the underlying genetic components of depression can open new avenues for the develop- ment of novel depression drugs. Specifically, if a Correspondence: Dr D Shattuck, Myriad Genetics, 320 Wakara genetic variant segregates with MDD in families, the Way, Salt Lake City UT 84108, USA. gene in which that variant occurs is likely to be E-mail: [email protected] involved in the pathobiology of disease. Such a gene Dr DA Katz, Abbott Laboratories, 100 Abbott Park Road, R48B/ can be a target for development of novel antidepres- AP6C-6, Abbott Park IL 60064, USA. E-mail: [email protected] sants, or lead to identification of previously unknown Received 9 July 2007; revised 14 September 2007; accepted 23 physiological pathways that can be modulated for September 2007; published online 12 February 2008 effective therapy of depression. Interacting genetic risk factors in MDD CD Neff et al 622 Materials and methods used to amplify LHPP exons are shown in Supple- mentary Materials and methods. All samples were Subjects and linkage analysis amplified with Taq Platinum (Invitrogen, Carlsbad, The ascertainment and characteristics of a majority of CA, USA) DNA polymerase. PCR cycles included an the linkage pedigrees has been described.6 Informed initial denaturation at 96 1C (12 s), annealing at 57 1C consent was obtained from each subject. The institu- (15 s) and extension at 72 1C (30–60 s). Excess tional review boards of Intermountain Health Care primers and deoxynucleotide triphosphates from and Valley Mental Health approved the research M13-tailed PCR products were digested with exonu- protocol. Two meaningful differences between the clease I (United States Biochemicals, Cleveland, present study and our previously published work are OH, USA) and shrimp alkaline phosphatase as following: first, that the definition of affected (Amersham, Piscataway, NJ, USA). PCR products status in this study did not include bipolar disorder; were sequenced with M13 forward and reverse second, that 22 additional pedigrees were ascertained fluorescent Big Dye-labeled primers (Applied using the previous criteria. The average pedigree size Biosystems, Foster City, CA, USA) on Applied was 16 individuals (range 6–55) including a mean of Biosystems 3730 sequencers. 8 affected individuals (range 4–31). The analysis leading to discovery of the chromosome 10 linkage Statistical analysis region included 1054 individuals (744 female subjects Based on several prior associations with MDD or and 310 male subjects) with MDD (DSM-IV-TR related phenotypes,8–15 the one-tailed Fisher’s exact sections 296.2x or 296.3x). Affected individuals were test (a = 0.05) was used to test the association of major genotyped and genome-wide linkage analysis was depression in the Utah population with HTR1A performed as described,6 except that only individuals –1019G allele or –1019GG genotype. carrying one or two HTR1A À1019G alleles were To establish the evidence that LHPP acts as a assigned affected status. depression gene in the chromosome 10 linkage region, allele frequencies on the 22 chromosomes Polymorphism discovery in linked pedigrees that cosegregated with MDD were compared, using Genomic DNA from members of the MDD pedigrees the two-tailed Fisher’s exact test (a = 0.05), to frequen- with the strongest linkage evidence was resequenced. cies in three sets of control chromosomes. A first set From each pedigree, two female subjects with MDD, of 60 control chromosomes included the 12 non- carrying one or two HTR1A À1019G alleles, and segregating chromosomes from genotyped, affected sharing a chromosome 10 haplotype that cosegregates pedigree members and 48 chromosomes from 24 with the disease were selected. This allowed direct unrelated individuals from Utah CEPH pedigrees. determination of whether each variant found during The second set of 180 control chromosomes was from resequencing cosegregated with the disease. In the 90 additional Utah CEPH pedigree grandparents. The case of common variants, using this strategy to predict third set of 708 control chromosomes was from 354 cosegregation could overestimate the actual cosegre- unrelated samples collected in Utah. Replication was gation of the variant with disease, but for such used, rather than a-level adjustment, to avoid an variants resequencing of additional family members inflated type I error rate. was undertaken to verify that the variant was indeed For population association analyses, cases were on the disease associated haplotype. Haplotype individuals with confirmed diagnosis of MDD sharing was determined using the program MCLINK7 (DSM-IV-TR sections 296.2x or 296.3x). Ashkenazi during linkage analysis. samples were individuals who reported four grand- Thirty-six genes (Supplementary Table S1) were parents of Ashkenazi descent. These samples were identified within the minimal recombinant region collected by PrecisionMed (Solana Beach, CA, USA). using both publicly available NCBI human genome Utah and Ashkenazi individuals ascertained without assemblies and assembly of publicly available se- respect to depression status were used as controls. quence data using a proprietary algorithm (Compu- Initial logistic regression models included LHPP gen, Israel). Several genes were extended using rapid genotype, HTR1A genotype, gender and both geno- amplification of cDNA ends. type-by-genotype and genotype-by-gender interaction PCR amplification was used to generate products to terms. LHPP and HTR1A genotypes were each screen for segregating variants in all exons and dichotomized such that risk allele carriers (hetero- proximal promoter regions of the identified genes. zygous or homozygous) were compared to non- When possible to conserve
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