Genome-wide linkage analysis and evidence of gene-by-gene interactions in a sample of 362 multiplex Parkinson disease families

Parkinson disease (PD) is the second most common neurodegenerative disorder. We studied 754 affected individuals, comprising 425 sibling pairs, to identify PD susceptibility genes. Screening of the parkin gene was performed in a subset of the sample having earlier age of PD onset or a positive LOD score with a marker in the parkin gene. All subjects were evaluated using a rigorous neurological assessment. Two diagnostic models were considered for genome-wide, non-parametric linkage analyses. Model I included only those individuals with a more stringent diagnosis of verified PD (216 sibling pairs) and resulted in a maximum LOD score of 3.4 on chromosome 2. Model II included all affected individuals (425 sibling pairs) and yielded a LOD score of 3.1 on the X chromosome. Our large sample was then employed to test for gene-by-gene (epistatic) interactions. A genome screen using the 23 families with PD patients having a mutation in only one allele of the parkin gene detected evidence of linkage to chromosome 10 (LOD=2.3). The 85 families with a very strong family history of PD were employed in a genome screen and, in addition to strong evidence of linkage to chromosome 2 (LOD=4.9), also produced a LOD of 2.4 on chromosome 14. A genome screen performed in the 277 families without a strong family history of PD detected linkage to chromosomes 10 (LOD=2.4) and X (LOD=3.2). These findings demonstrate consistent evidence of linkage to chromosomes 2 and X and also support the hypothesis that gene-by-gene interactions are important in PD susceptibility.     

Genomic screen for loci associated with alcohol dependence in Mission Indians.

Alcohol dependence is a leading cause of morbidity and mortality in Native Americans, yet biological factors underlying the disorder in this ethnic group remain elusive. This study's aims were to map susceptibility loci for DSM-III-R alcohol dependence and two narrower alcohol-related phenotypes in Mission Indian families. Each participant gave a blood sample and completed an interview using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) that was used to make alcohol dependence diagnoses and the narrower phenotypes of withdrawal, and drinking severity. Genotypes were determined for a panel 791 microsatellite polymorphisms. Analyses of multipoint variance component LOD scores for the dichotomous DSM-III-R phenotype revealed no peak LOD scores that exceeded 2.0 at any chromosome location. Two chromosomes, 4 and 12, had peak LOD scores that exceeded 2 for the alcohol use severity phenotype and three chromosomes 6, 15, 16 were found to have peaks with LOD scores that exceeded 2 for the withdrawal phenotype. Evidence for linkage to chromosomes 4 and 15, and 16 have been reported previously for alcohol related phenotypes whereas no evidence has as yet been reported for chromosomes 6 and 12. Combined linkage and association analysis suggest that alcohol dehydrogenase 1B gene polymorphisms are partially responsible for the linkage result on chromosome 4 in this population. These results corroborate the importance of several chromosomal regions highlighted in prior segregation studies in alcoholism and further identify new regions of the genome that may be unique to either the restricted phenotypes evaluated or this population of Mission Indians.     

An extended genome scan in 442 Canadian multiple sclerosis-affected sibships: a report from the Canadian Collaborative Study Group

Multiple sclerosis (MS) is a complex trait with a sibling relative risk (lambda(sibs)) between 18 and 36. We report a multistage genome scan of 552 sibling pairs from 442 families, the largest MS family sample assessed for linkage. The first stage consisted of a genome scan for linkage with 498 microsatellite markers at an average spacing of 7 cM in 219 sibling pairs. The second stage involved further genotyping of markers from positive regions in an independent sample of 333 affected sibling pairs. The global distribution of allele sharing for all markers showed a shift towards greater sharing within the affected sibling pair group but not in the discordant sibling pair group. This shift indicates that the number of contributing genetic factors is likely to be moderate to large. Only markers at chromosome 6p showed significant evidence for linkage (MLOD=4.40), while other regions were only suggestive (1p, 2q, 5p, 9q, 11p, 12q, 18p, 18q and 21q) with MLODs greater than 1.0. The replication analysis involving all 552 affected sibling pairs confirmed suggestive evidence for five locations, namely, 2q27 (MLOD=2.27), 5p15 (MLOD=2.09), 18p11 (MLOD=1.68), 9q21 (MLOD=1.58) and 1p31 (MLOD=1.33). Suggestive linkage evidence for a previously reported location on chromosome 17q (MLOD=1.67) and a prior association with marker D17S789 was replicated. We showed that the overall excess allele sharing we observed for the entire sample was due to increased allele sharing within the DRB1*15 negative subgroup alone. This observation is most consistent with a model of genetic heterogeneity between HLA and other genetic loci. These findings offer guidance for future genetic studies including dense SNP linkage disequilibrium analysis.     

Results of a genomewide linkage scan: support for chromosomes 9 and 11 loci increasing risk for cigarette smoking.

Cigarette smoking is highly destructive to individuals and society, and is moderately heritable. We completed a genomewide linkage scan to map loci increasing risk for cigarette smoking in a set of families originally identified because they segregate panic disorder (PD). One hundred forty two genotyped individuals in a total of 12 families were studied (214 subjects analyzed, including non-genotyped individuals). Of these individuals, 69 were "affected" with habitual cigarette smoking (i.e., they smoked more than one pack per day for at least a year, or at least 1/2 pack per day for at least 10 years), 49 were "unaffected" (i.e., they smoked less than 1/2 pack per day for less than 1 year), and 24 were scored as "unknown." Nine families from the panic series were excluded from these analyses because they lacked multiple affected individuals with habitual cigarette smoking. In an initial genomewide scan, we genotyped a total of 416 markers (398 autosomal, 18 X-chromosome) with an average spacing of less than 10 cM, spanning the genome. Linkage analysis (pairwise, or single-point, and multi-point) was performed using ALLEGRO. An additional 14 markers were genotyped in a high-density panel to follow-up on an identified region of interest on chromosome 11p. The three highest multi-point Zlr scores (3.43, 3.04, and 3.01; P = 0.0003, P = 0.0012, and P = 0.0013, respectively), which each reflect "suggestive" evidence for linkage, were observed in multi-point linkage analyses using Allegro on chromosomes 11p and 9, near markers D11S4046, D9S283, and D9S1677, respectively. D11S4046 is in a region where linkage to alcohol dependence and linkage disequilibrium to substance dependence have previously been identified. The chromosome 9 region we identified as possibly linked to cigarette smoking in anxiety families, was previously identified as significantly linked to PD in Icelandic pedigrees. We also identified evidence supporting linkage (Zlr score > 2.3, P < 0.01) to regions of chromosomes 14, 16, and X. There was a significant phenotypic association between PD and cigarette smoking (P < 0.001). Conclusions: We identified evidence for two loci increasing risk for cigarette smoking that map to chromosomes 9 and 11. There is now evidence supporting linkage or association of chromosome 11 markers with alcohol dependence, illegal drug abuse and dependence, and cigarette smoking. Interestingly, one of our most promising linkage regions, includes a region previously identified as linked to PD.     

A genome scan of neuroticism in nicotine dependent smokers.

Neuroticism is a personality factor that has consistently been demonstrated to be associated with anxiety, depression, and other "internalizing" disorders. We analyzed a genome scan for neuroticism on a sample of 129 sib-pair families (113 with a single sibling pair, 18 with multiple sibling pairs) containing a total of 201 possible sibling pairs, ascertained for concordance on nicotine dependence. Using Merlin-Regress, we replicated peaks for neuroticism described by prior studies, on chromosomes 1 and 11 with LOD scores of 2.52 and 1.97 (P-value of 0.003 and 0.0108) respectively, and have some evidence for a novel finding on chromosome 12 with a LOD of 2.85 (P-value of 0.0014).     

Family-based study of the association of the dopamine D2 receptor gene (DRD2) with habitual smoking

A recent study showed an association between the dopamine D2 receptor gene (DRD2) and smoking. The purpose of this study was to determine if the familial transmission of smoking is linked to variation at the DRD2 locus in a genetically informative sample. Subjects were identified in alcohol treatment centers and their relatives were recruited for study. All subjects were interviewed to assess alcohol dependence, smoking habits, and psychiatric disorders. Two polymorphisms within the DRD2 gene were analyzed, including the TaqIA polymorphism. The sample consisted of 138 nuclear families with at least one offspring with habitual smoking, and analysis was by the transmission disequilibrium test (TDT), which avoids problems due to population stratification. There was no significant difference in the frequency between DRD2 alleles transmitted and not transmitted to habitual smokers. There also was no evidence for unequal transmission of DRD2 alleles for the phenotypes "ever smoker" or comorbid alcohol dependence and habitual smoking. This study does not support linkage of the DRD2 with smoking.     

Initial genomic scan of the NIMH genetics initiative bipolar pedigrees: Chromosomes 3, 5, 15, 16, 17, and 22

As part of the four-center NIMH Genetics Initiative on Bipolar Disorder we carried out a genomic scan of chromosomes 3, 5, 15, 16, 17, and 22. Genotyping was performed on a set of 540 DNAs from 97 families, enriched for affected relative pairs and parents where available. We report here the results of the initial 74 markers that have been typed on this set of DNAs. The average distance between markers (θ) was 12.3 cM. Nonparametric analysis of excess allele sharing among affected sibling pairs used the SIBPAL program of the S.A.G.E. package to test three hierarchical models of affected status. D16S2619 gave some evidence of linkage to bipolar disorder, with P = 0.006 for Model II (in which bipolar 1, bipolar 2 and schizoaffective-bipolar type individuals are considered affected). Nearby markers also showed increased allele sharing. A second interesting region was toward the telomere of chromosome 5q, where D5S1456 and nearby markers showed increased allele sharing; for D5S1456, P = 0.05, 0.015 and 0.008 as the models of affected status become more broad. MOD score analysis also supported the possible presence of a susceptibility locus in this region of chromosome 5. A pair of adjacent markers on chromosome 3, D3S2405 and D3S3038, showed a modest increased allele sharing in the broad model. Several isolated markers had excess allele sharing at the P < 0.05 level under a single model. D15S217 showed a MOD score of 2.37 ( P < 0.025). Multipoint analysis flagged the region of chromosome 22 around D22S533 as the most interesting. Thus, several regions showed modest evidence for linkage to bipolar disorder in this initial genomic scan of these chromosomes, including broad regions near previous reports of possible linkage. Am. J. Med. Genet. 74:238–246, 1997. © Wiley-Liss, Inc.     

Full genome screen for Alzheimer disease: stage II analysis

We performed a two-stage genome screen to search for novel risk factors for late-onset Alzheimer disease (AD). The first stage involved genotyping 292 affected sibling pairs using 237 markers spaced at approximately 20 cM intervals throughout the genome. In the second stage, we genotyped 451 affected sibling pairs (ASPs) with an additional 91 markers, in the 16 regions where the multipoint LOD score was greater than 1 in stage I. Ten regions maintained LOD scores in excess of 1 in stage II, on chromosomes 1 (peak B), 5, 6, 9 (peaks A and B), 10, 12, 19, 21, and X. Our strongest evidence for linkage was on chromosome 10, where we obtained a peak multipoint LOD score (MLS) of 3.9. The linked region on chromosome 10 spans approximately 44 cM from D10S1426 (59 cM) to D10S2327 (103 cM). To narrow this region, we tested for linkage disequilibrium with several of the stage II microsatellite markers. Of the seven markers we tested in family-based and case control samples, the only nominally positive association we found was with the 167 bp allele of marker D10S1217 (chi-square=7.11, P=0.045, df=1).     

Genome-wide Linkage Scan to Identify Loci for Age at First Cigarette in Dutch Sibling Pairs

The heritability of age at first cigarette was estimated in 5883 Dutch twins and siblings registered with the Netherlands Twin Register. Heritability was 60% for males and 39% for females. Shared environmental influences were found in females only (30%). Linkage analyses were performed on data of 422 DZ twins and siblings from 175 families, forming 368 sibling pairs. Genomic regions that may harbor susceptibility loci for age at first cigarette with LOD score greater than 2 were detected on chromosomes 5, 14 and 22. A simultaneous analysis of these three genomic regions showed that most of the variance was explained by the linkage effect on chromosome 5 (205 cM). This peak encloses the D1A dopamine receptor gene which is a functional candidate gene for smoking behavior.     

High-density SNP analysis of 642 Caucasian families with rheumatoid arthritis identifies two new linkage regions on 11p12 and 2q33

We have completed a genome wide linkage scan using >5700 informative single-nucleotide polymorphism (SNP) markers (Illumina IV SNP linkage panel) in 642 Caucasian families containing affected sibling pairs with rheumatoid arthritis (RA), ascertained by the North American Rheumatoid Arthritis Consortium. The results show striking new evidence of linkage at chromosomes 2q33 and 11p12 with logarithm of odds (LOD) scores of 3.52 and 3.09, respectively. In addition to a strong and broad linkage interval surrounding the major histocompatibility complex (LOD>16), regions with LOD>2.5 were observed on chromosomes 5 and 10. Additional linkage evidence (LOD scores between 1.46 and 2.35) was also observed on chromosomes 4, 7, 12, 16 and 18. This new evidence for multiple regions of genetic linkage is partly explained by the significantly increased information content of the Illumina IV SNP linkage panel (75.6%) compared with a standard microsatellite linkage panel utilized previously (mean 52.6%). Stratified analyses according to whether or not the sibling pair members showed elevated anticyclic citrullinated peptide titers indicates significant variation in evidence for linkage among strata on chromosomes 4, 5, 6 and 7. Overall, these new linkage data should reinvigorate efforts to utilize positional information to identify susceptibility genes for RA.     

Evidence for an inflammatory bowel disease locus on chromosome 3p26: linkage,transmission/disequilibrium and partitioning of linkage

Crohn's disease and ulcerative colitis, the two major forms of idiopathic inflammatory bowel disease (IBD), are heritable, complex traits that appear to share some but not all susceptibility loci. We report that transmission/disequilibrium test analysis of a Crohn's disease genome scan dataset has detected an inflammatory bowel disease locus on chromosome 3p26 (nominal P=0.000052 and genome-wide corrected P=0.039 at D3S1297). An allele sharing method shows significant linkage (multipoint lod=3.69) in a larger, independent sample of inflammatory bowel disease-affected sibling pairs. A survey of 16 chromosome 3p26 short tandem repeat polymorphisms in a combined sample of 234 independent nuclear families with 324 IBD-affected sibling pairs shows significant linkage to chromosome 3p26 (multipoint lod=3.78) and significant transmission/disequilibrium test results at two adjacent markers (nominal P values in two different transmission/disequilibrium analysis methods=0.00011 and 0.0011 for the first marker, and 0.00071 and 0.00013 for the second marker). There is highly significant under-transmission of a common allele and modest over-transmission of other alleles at both markers. Families with no transmission to affected individuals of the under-transmitted alleles show significant linkage (multipoint lod=4.50) that is significantly greater in four simulation studies (P=0.0001, 0.0000625, 0.0000625 and 0.0000625, respectively) than the linkage evidence in families with transmission of the under-transmitted alleles (multipoint lod=0.12). Thus, the existence of an inflammatory bowel disease locus on chromosome 3p26 is supported by significant linkage, transmission/disequilibrium and partitioning of linkage evidence.     

Chromosomes 12 and 16 workshop.

Recent linkage results independently derived from a large French Canadian pedigree and Danish kindreds coupled with supportive data from other studies provide compelling evidence for a bipolar disorder susceptibility locus on chromosome 12q23-q24. The idea is further strengthened by the finding that Darier's disease, which maps to this region, has been shown to cosegregate with affective disorder in a family. This linkage finding, however, was not supported in other independent genome scans. On chromosome 16, bipolar families from Denmark exhibited suggestive linkage with D16S510, on 16p13. Multipoint nonparametric analysis on the NIMH Genetics Initiative bipolar pedigrees yielded increased allele sharing that maximized approximately 18 cM proximal to the latter locus. In contrast, evidence of linkage was not detected in other panels of bipolar families that were presented. At 16p13, a maximum multipoint lod score of 4 for a latent class-derived phenotype that has aspects of alcohol dependence was found in a genome scan of 105 families from the Collaborative Study of the Genetics of Alcoholism, identifying a potential vulnerability locus.     

Failure to establish linkage on the X chromosome in 301 families with schizophrenia or schizoaffective disorder

The hypothesis that a gene for susceptibility to psychosis (specifically in the X-Y homologous class) is located on the sex chromosomes has been proposed. Such a gene would account for the excess of sex chromosome anomalous males and females in populations of patients with psychosis, a tendency towards concordance by sex within families, and sex differences associated with psychosis and its underlying brain pathology. In earlier studies we observed small positive LOD scores in Xp11, and in a more recent and larger cohort of 178 sibling pairs, a peak multipoint nonparametric LOD score of 1. 55 at the locus DXS8032 in Xq21. The present study with a new set of markers extended the cohort to 301 ill sibling pairs and their parents. Despite the increase in sample size, the LOD score did not increase. A peak NPL of 1.55 was observed at the locus DXS1068 in proximal Xp, a region remote from the previous report. Separating families into those who were more likely to have X chromosome inheritance (maternal with no male to male transmission) did not yield stronger findings. In spite of the evidence that psychosis is related to a sex-dependent dimension of cerebral asymmetry, it is concluded that no consistent linkage of schizophrenia to the X chromosome can be demonstrated. In the context of the general failure of replication of linkage in psychosis, the possibility that the genetic predisposition to psychosis is contributed to by epigenetic modification rather than variations in the nucleotide sequence has to be considered.     

Full genome screen for Alzheimer disease: Stage II analysis*

We performed a two‐stage genome screen to search for novel risk factors for late‐onset Alzheimer disease (AD). The first stage involved genotyping 292 affected sibling pairs using 237 markers spaced at approximately 20 cM intervals throughout the genome. In the second stage, we genotyped 451 affected sibling pairs (ASPs) with an additional 91 markers, in the 16 regions where the multipoint LOD score was greater than 1 in stage I. Ten regions maintained LOD scores in excess of 1 in stage II, on chromosomes 1 (peak B), 5, 6, 9 (peaks A and B), 10, 12, 19, 21, and X. Our strongest evidence for linkage was on chromosome 10, where we obtained a peak multipoint LOD score (MLS) of 3.9. The linked region on chromosome 10 spans approximately 44 cM from D10S1426 (59 cM) to D10S2327 (103 cM). To narrow this region, we tested for linkage disequilibrium with several of the stage II microsatellite markers. Of the seven markers we tested in family‐based and case control samples, the only nominally positive association we found was with the 167 bp allele of marker D10S1217 (chi‐square = 7.11, P = 0.045, df = 1). © 2002 Wiley‐Liss, Inc.     

Linkage Analyses of IQ in the Collaborative Study on the Genetics of Alcoholism (COGA) Sample

Intelligence, as measured by standardized psychological tests, has been shown to be highly heritable, though identifying specific genes influencing general intelligence has proven difficult. We conducted genome-wide linkage analyses to identify chromosomal regions containing genes influencing intelligence, as measured by WAIS full-scale IQ (FSIQ), performance IQ (PIQ) and verbal IQ (VIQ). Non-parametric multipoint linkage analyses were conducted with Merlin-regress software, using a sample of 1111 genotyped and phenotyped individuals from 201 families, ascertained as part of the Collaborative Study on the Genetics of Alcoholism (COGA). The strongest evidence of linkage was obtained for FSIQ on chromosome 6 (LOD=3.28, 12 cM) near the marker D6S1006. This region was also implicated with suggestive linkage in a recently published genome screen of IQ in Australian and Dutch twin pairs, and it has been implicated in linkage studies of developmental dyslexia. Our findings provide further support that chromosome 6p contains gene(s) affecting intelligence.     

Family‐based study of the association of the dopamine D2 receptor gene (DRD2) with habitual smoking

A recent study showed an association between the dopamine D2 receptor gene (DRD2) and smoking. The purpose of this study was to determine if the familial transmission of smoking is linked to variation at the DRD2 locus in a genetically informative sample. Subjects were identified in alcohol treatment centers and their relatives were recruited for study. All subjects were interviewed to assess alcohol dependence, smoking habits, and psychiatric disorders. Two polymorphisms within the DRD2 gene were analyzed, including the TaqIA polymorphism. The sample consisted of 138 nuclear families with at least one offspring with habitual smoking, and analysis was by the transmission disequilibrium test (TDT), which avoids problems due to population stratification. There was no significant difference in the frequency between DRD2 alleles transmitted and not transmitted to habitual smokers. There also was no evidence for unequal transmission of DRD2 alleles for the phenotypes “ever smoker” or comorbid alcohol dependence and habitual smoking. This study does not support linkage of the DRD2 with smoking. Am. J. Med. Genet. 90:299–302, 2000. © 2000 Wiley‐Liss, Inc.     

Replication and extension studies of inflammatory bowel disease susceptibility regions confirm linkage to chromosome 6p (IBD3)

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the intestine, commonly diagnosed as either ulcerative colitis (UC) or Crohn's disease (CD). Epidemiological studies have consistently shown that both genetic and environmental factors influence the pathogenesis of IBD. A number of genome scans have been conducted in cohorts of IBD families with affected sibling pairs (ASPs) to identify chromosomal regions that harbour IBD susceptibility genes. Several putative linked loci have been identified, including two loci on chromosomes 16 and 12, IBD1 and IBD2, which have subsequently been replicated by independent region-specific studies. We have conducted both a replication study on another linkage region, chromosome 6p (IBD3), and extension studies on two other regions, chromosomes 3p and 7q. Microsatellite markers across each region were genotyped in 284 IBD ASPs from 234 families. A nonparametric peak multipoint LOD score of 3.0 was observed near D6S291, replicating the previous linkage to chromosome 6p (IBD3). Nominal evidence of linkage was observed at both the 3p and 7q regions.     

Chromosomes 12 and 16 workshop

Recent linkage results independently derived from a large French Canadian pedigree and Danish kindreds coupled with supportive data from other studies provide compelling evidence for a bipolar disorder susceptibility locus on chromosome 12q23-q24. The idea is further strengthened by the finding that Darier's disease, which maps to this region, has been shown to cosegregate with affective disorder in a family. This linkage finding, however, was not supported in other independent genome scans. On chromosome 16, bipolar families from Denmark exhibited suggestive linkage with D16S510, on 16p13. Multipoint nonparametric analysis on the NIMH Genetics Initiative bipolar pedigrees yielded increased allele sharing that maximized ∼18 cM proximal to the latter locus. In contrast, evidence of linkage was not detected in other panels of bipolar families that were presented. At 16p13, a maximum multipoint lod score of 4 for a latent class-derived phenotype that has aspects of alcohol dependence was found in a genome scan of 105 families from the Collaborative Study of the Genetics of Alcoholism, identifying a potential vulnerability locus. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:255–259, 1999. Published 1999 Wiley-Liss, Inc.     

Haplotype spanning TTC12 and ANKK1, flanked by the DRD2 and NCAM1 loci, is strongly associated to nicotine dependence in two distinct American populations

Nicotine dependence (ND) is a moderately heritable trait. We ascertained a set of 1615 subjects in 632 families [319 African-American (AA) and 313 European-American (EA)] based on affected sibling pairs with cocaine or opioid dependence. Subjects were interviewed with the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA). Previously, we identified a modest linkage peak (LOD score =1.97) for ND in the EA part of the sample on chromosome 11q23, a region that includes the NCAM1-TTC12-ANKK1-DRD2 gene cluster. DRD2 and NCAM1 are functional candidate genes for substance dependence; the TTC12 and ANKK1 loci are not well characterized. We genotyped a set of 43 single nucleotide polymorphisms (SNPs) spanning this region, and performed family-based association and haplotype analysis. There was relatively weak evidence for association of the flanking DRD2 and NCAM1 markers to ND, but very strong evidence of association of multiple SNPs at TTC12 and ANKK1 in both populations (minimal P=0.0007 in AAs and minimal P=0.00009 in EAs), and in the pooled sample, as well as strong evidence for highly significant association of a single haplotype spanning TTC12 and ANKK1 to ND in the pooled sample (P=0.0000001). We conclude that a risk locus for ND, important both in AAs and EAs, maps to a region that spans TTC12 and ANKK1. Functional studies of these loci are warranted. These results provide additional information useful in evaluating the many earlier discrepant findings regarding association of DRD2 with substance dependence.     

Linkage analyses of stimulant dependence,craving, and heavy use in American Indians

Amphetamine‐type substances are the second most widely used illicit drugs in the United States. There is evidence to suggest that stimulant use (cocaine and methamphetamine) has a heritable component, yet the areas of the genome underlying these use disorders are yet to be identified. This study's aims were to map loci linked to stimulant dependence, heavy use, and craving in an American Indian community at high risk for substance dependence. DSM diagnosis of stimulant dependence, as well as indices of stimulant “craving,” and “heavy use,” were obtained using the Semi‐Structured Assessment for the Genetics of Alcoholism (SSAGA). Genotypes were determined for a panel of 791 microsatellite polymorphisms in 381 members of multiplex families using SOLAR. Stimulant dependence, stimulant “craving,” and “heavy stimulant use,” were all found to be heritable. Analyses of multipoint variance component LOD scores, failed to yield evidence of linkage for stimulant dependence. For the stimulant “craving” phenotype, linkage analysis revealed a locus that had a LOD score of 3.02 on chromosome 15q25.3‐26.1 near the nicotinic receptor gene cluster. A LOD score of 2.05 was found at this same site for “heavy stimulant use.” Additional loci with LOD scores above 2.00 were found for stimulant “craving” on chromosomes 12p13.33‐13.32 and 18q22.3. These results corroborate the importance of “craving” as an important phenotype that is associated with regions on chromosome 12, 15, and 18, that have been highlighted in prior segregation studies in this and other populations for substance dependence‐related phenotypes. © 2011 Wiley‐Liss, Inc.